Imperial College London

ProfessorThomasBrand

Faculty of MedicineNational Heart & Lung Institute

Chair in Developmental Dynamics
 
 
 
//

Contact

 

+44 (0)20 7594 8744t.brand Website CV

 
 
//

Assistant

 

Miss Cheryl Costello +44 (0)20 7594 3001

 
//

Location

 

433ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

147 results found

Tibbo AJ, Mika D, Dobi S, Ling J, McFall A, Tejeda GS, Blair C, MacLeod R, MacQuaide N, Gök C, Fuller W, Smith BO, Smith GL, Vandecasteele G, Brand T, Baillie GSet al., 2022, Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins., J Mol Cell Cardiol

Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye domain containing (POPDC) proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that POPDC proteins exist in complexes with members of the PDE4 family in cardiac myocytes. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 modulates cycle length of spontaneous Ca2+ transients firing in intact mouse sinoatrial nodes.

Journal article

Shetty MS, Ris L, Schindler RFR, Mizuno K, Fedele L, Giese KP, Brand T, Abel Tet al., 2021, Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity, Cerebral Cortex, ISSN: 1047-3211

Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have a unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wildtype mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP-PKA-PDE signaling.

Journal article

Gruscheski L, Brand T, 2021, The role of POPDC proteins in cardiac pacemaking and conduction, Journal of Cardiovascular Development and Disease, Vol: 8, ISSN: 2308-3425

The Popeye domain-containing (POPDC) gene family, consisting of Popdc1 (also known as Bves), Popdc2, and Popdc3, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been identified as cAMP effector proteins and have been proposed to be part of the protein network involved in cAMP signaling. However, their exact biochemical activity is presently poorly understood. Loss-of-function mutations in animal models causes abnormalities in skeletal muscle regeneration, conduction, and heart rate adaptation after stress. Likewise, patients carrying missense or nonsense mutations in POPDC genes have been associated with cardiac arrhythmias and limb-girdle muscular dystrophy. In this review, we introduce the POPDC protein family, and describe their structure function, and role in cAMP signaling. Furthermore, the pathological phenotypes observed in zebrafish and mouse models and the clinical and molecular pathologies in patients carrying POPDC mutations are described.

Journal article

Abu Nahia K, Migdal M, Quinn TA, Poon K-L, Lapinski M, Sulej A, Liu J, Mondal SS, Pawlak M, Bugajski L, Piwocka K, Brand T, Kohl P, Korzh V, Winata Cet al., 2021, Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region, Cellular and Molecular Life Sciences, Vol: 78, Pages: 6669-6687, ISSN: 1420-682X

The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

Journal article

Holt I, Fuller HR, Schindler RFR, Shirran SL, Brand T, Morris GEet al., 2020, An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs, BMC Molecular and Cell Biology, Vol: 21, Pages: 1-13

BackgroundPopeye domain-containing proteins 1 and 2 (POPDC1 and POPDC2) are transmembrane proteins involved in cyclic AMP-mediated signalling processes and are required for normal cardiac pacemaking and conduction. In order to identify novel protein interaction partners, POPDC1 and 2 proteins were attached to beads and compared by proteomic analysis with control beads in the pull-down of proteins from cultured human skeletal myotubes.ResultsThere were highly-significant interactions of both POPDC1 and POPDC2 with XIRP1 (Xin actin binding repeat-containing protein 1), actin and, to a lesser degree, annexin A5. In adult human skeletal muscle, both XIRP1 and POPDC1/2 were present at the sarcolemma and in T-tubules. The interaction of POPDC1 with XIRP1 was confirmed in adult rat heart extracts. Using new monoclonal antibodies specific for POPDC1 and POPDC2, both proteins, together with XIRP1, were found mainly at intercalated discs but also at T-tubules in adult rat and human heart.ConclusionsMutations in human POPDC1, POPDC2 and in human XIRP1, all cause pathological cardiac arrhythmias, suggesting a possible role for POPDC1/2 and XIRP1 interaction in normal cardiac conduction.

Journal article

Fedele L, Brand T, 2020, The intrinsic cardiac nervous system and its role in cardiac pacemaking and conduction, Journal of Cardiovascular Development and Disease, Vol: 7, Pages: 54-54, ISSN: 2308-3425

The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac nervous system (ICNS) includes the network of the intracardiac ganglia and interconnecting neurons. The cardiac ganglia contribute to the tight modulation of cardiac electrophysiology, working as a local hub integrating the inputs of the extrinsic innervation and the ICNS. A better understanding of the role of the ICNS for the modulation of the cardiac conduction system will be crucial for targeted therapies of various arrhythmias. We describe the embryonic development, anatomy, and physiology of the ICNS. By correlating the topography of the intracardiac neurons with what is known regarding their biophysical and neurochemical properties, we outline their physiological role in the control of pacemaker activity of the sinoatrial and atrioventricular nodes. We conclude by highlighting cardiac disorders with a putative involvement of the ICNS and outline open questions that need to be addressed in order to better understand the physiology and pathophysiology of the ICNS.

Journal article

Rinné S, Ortiz-Bonnin B, Stallmeyer B, Kiper AK, Lisa Fortmüller L, Schindler RFR, Herbort-Brand U, Kabir NS, Dittmann S, Friedrich C, Zumhagen S, Gualandi F, Selvatici R, Rapezzi C, Arbustini E, Ferlini A, Larissa F, Schulze-Bahr E, Brand T, Decher Net al., 2020, POPDC2 a novel susceptibility gene for conduction disorders, Journal of Molecular and Cellular Cardiology, Vol: 145, Pages: 74-83, ISSN: 0022-2828

Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2W188*), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K2P) channel TREK 1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2W188* causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2W188* knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2W188* loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK 1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.

Journal article

Amunjela J, Swan A, Brand T, 2019, The role of the Popeye domain containing gene family in organ homeostasis, Cells, Vol: 8, ISSN: 2073-4409

The Popeye domain containing (POPDC) gene family consists of POPDC1 (also known as BVES), POPDC2 and POPDC3 and encode a novel class of cyclic adenosine monophosphate (cAMP) effector proteins. Despite first reports of their isolation and initial characterization at the protein level dating back already 20 years, only recently have major advances in defining their biological functions and disease association been made. Loss-of-function experiments in mouse and zebrafish established an important role in skeletal muscle regeneration, heart rhythm control and stress signaling. Patients suffering from muscular dystrophy and atrioventricular block were found to carry missense and nonsense mutations in either of the three POPDC genes, which suggests an important function in the control of striated muscle homeostasis. However, POPDC genes are also expressed in a number of epithelial cells and function as tumor suppressor genes involved in the control of epithelial structure, tight junction formation and signaling. Suppression of POPDC genes enhances tumor cell proliferation, migration, invasion and metastasis in a variety of human cancers, thus promoting a malignant phenotype. Moreover, downregulation of POPDC1 and POPDC3 expression in different cancer types has been associated with poor prognosis. However, high POPDC3 expression has also been correlated to poor clinical prognosis in head and neck squamous cell carcinoma, suggesting that POPDC3 potentially plays different roles in the progression of different types of cancer. Interestingly, gain of POPDC1 function in tumor cells inhibits cell proliferation, migration and invasion thereby reducing malignancy. Furthermore, POPDC proteins have been implicated in the control of cell cycle genes and epidermal growth factor and Wnt signaling. Work in tumor cell lines suggest that cyclic nucleotide binding may also be important in epithelial cells. Thus, POPDC proteins have a prominent role in tissue homeostasis and cellular signa

Journal article

Brown P, Tan A-C, El-Esawi MA, Liehr T, Blanck O, Gladue DP, Almeida GMF, Cernava T, Sorzano CO, Yeung AWK, Engel MS, Chandrasekaran AR, Muth T, Staege MS, Daulatabad SV, Widera D, Zhang J, Meule A, Honjo K, Pourret O, Yin C-C, Zhang Z, Cascella M, Flegel WA, Goodyear CS, van Raaij MJ, Bukowy-Bieryllo Z, Campana LG, Kurniawan NA, Lalaouna D, Huttner FJ, Ammerman BA, Ehret F, Cobine PA, Tan E-C, Han H, Xia W, McCrum C, Dings RPM, Marinello F, Nilsson H, Nixon B, Voskarides K, Yang L, Costa VD, Bengtsson-Palme J, Bradshaw W, Grimm DG, Kumar N, Martis E, Prieto D, Sabnis SC, Amer SEDR, Liew AWC, Perco P, Rahimi F, Riva G, Zhang C, Devkota HP, Ogami K, Basharat Z, Fierz W, Siebers R, Tan K-H, Boehme KA, Brenneisen P, Brown JAL, Dalrymple BP, Harvey DJ, Ng G, Werten S, Bleackley M, Dai Z, Dhariwal R, Gelfer Y, Hartmann MD, Miotla P, Tamaian R, Govender P, Gurney-Champion OJ, Kauppila JH, Zhang X, Echeverria N, Subhash S, Sallmon H, Tofani M, Bae T, Bosch O, Cuiv PO, Danchin A, Diouf B, Eerola T, Evangelou E, Filipp FV, Klump H, Kurgan L, Smith SS, Terrier O, Tuttle N, Ascher DB, Janga SC, Schulte LN, Becker D, Browngardt C, Bush SJ, Gaullier G, Ide K, Meseko C, Werner GDA, Zaucha J, Al-Farha AA, Greenwald NF, Popoola SI, Rahman MS, Xu J, Yang SY, Hiroi N, Alper OM, Baker CI, Bitzer M, Chacko G, Debrabant B, Dixon R, Forano E, Gilliham M, Kelly S, Klempnauer K-H, Lidbury BA, Lin MZ, Lynch I, Ma W, Maibach EW, Mather DE, Nandakumar KS, Ohgami RS, Parchi P, Tressoldi P, Xue Y, Armitage C, Barraud P, Chatzitheochari S, Coelho LP, Diao J, Doxey AC, Gobet A, Hu P, Kaiser S, Mitchell KM, Salama MF, Shabalin IG, Song H, Stevanovic D, Yadollahpour A, Zeng E, Zinke K, Alimba CG, Beyene TJ, Cao Z, Chan SS, Gatchell M, Kleppe A, Piotrowski M, Torga G, Woldesemayat AA, Cosacak MI, Haston S, Ross SA, Williams R, Wong A, Abramowitz MK, Effiong A, Lee S, Abid MB, Agarabi C, Alaux C, Albrecht DR, Atkins GJ, Beck CR, Bonvin AMJJ, Bourke E, Brand T, Braun RJ, Bull JA, Cardoso P, Carter Det al., 2019, Large expert-curated database for benchmarking document similarity detection in biomedical literature search, Database: the journal of biological databases and curation, Vol: 2019, Pages: 1-66, ISSN: 1758-0463

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.

Journal article

Vissing J, Johnson K, Topf A, Nafissi S, Diaz-Manera J, French VM, Schindler RF, Sarathchandra P, Lokken N, Rinne S, Freund M, Decher N, Mueller T, Duno M, Krag T, Brand T, Straub Vet al., 2019, POPDC3 gene variants associate with a new Form of limb girdle muscular dystrophy, Annals of Neurology, Vol: 86, Pages: 832-843, ISSN: 0364-5134

ObjectiveThe Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.MethodsWe screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current.ResultsWe identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1.InterpretationOur findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843

Journal article

Brand T, 2019, POPDC proteins and cardiac function, Biochemical Society Transactions, Vol: 47, Pages: 1393-1404, ISSN: 0300-5127

The Popeye domain containing gene family encodes a novel class of cAMP effector proteinsin striated muscle tissue. In this short review, we first introduce the protein family anddiscuss their structure and function with an emphasis on their role in cyclic AMP signalling.Another focus of this review is the recently discovered role of POPDC genes as striatedmuscle disease genes, which have been associated with cardiac arrhythmia and musculardystrophy. The pathological phenotypes observed in patients will be compared withphenotypes present in null and knockin mutations in zebrafish and mouse. A number ofprotein-protein interaction partners have been discovered and the potential role of POPDCproteins to control the subcellular localization and function of these interacting proteins willbe discussed. Finally, we outline several areas, where research is urgently needed.

Journal article

Thompson JJ, Short SP, Parang B, Brown RE, Li C, Ng VH, Saito-Diaz K, Choksi YA, Washington MK, Smith JJ, Fingleton B, Brand T, Lee E, Coffey RJ, Williams CSet al., 2019, Blood vessel epicardial substance (BVES) reduces LRP6 receptor and cytoplasmic -catenin levels to modulate Wnt signaling and intestinal homeostasis, Carcinogenesis, Vol: 40, Pages: 1086-1098, ISSN: 1460-2180

Blood vessel epicardial substance (BVES, otherwise known as POPDC1) is an integral membrane protein known to regulate tight junction formation and epithelial-mesenchymal transition. BVES is underexpressed in a number of malignancies, including colorectal cancer. BVES loss leads to activation of the Wnt pathway, suggesting that decreased BVES expression functionally contributes to tumorigenesis. However, the mechanism by which BVES modulates Wnt signaling are unknown. Here we confirm that BVES loss increases -catenin protein levels, leads to Wnt pathway activation in a ligand-independent fashion, and coordinates with Wnt ligand to further increase Wnt signaling. We show that BVES loss increases levels and activation of the Wnt co-receptor, LRP6, in cell lines, murine adenoma tumoroids, and human-derived colonoids. We also demonstrate that BVES interacts with LRP6. Finally, murine tumor modelling using a Wnt-driven genetic model and a chemically-induced model of colorectal carcinogenesis demonstrates that BVES loss increases tumor multiplicity and dysplasia. Together, these results implicate BVES as an inhibitor of Wnt signaling, provide one of the first examples of a tight junction-associated protein regulating Wnt receptor levels, and expand the number of putative molecular targets for therapeutic intervention in colorectal cancer.

Journal article

Swan A, Gruscheski L, Boland L, Brand Tet al., 2019, The Popeye domain containing gene family encoding a family of cAMP-effector proteins with important functions in striated muscle and beyond, Journal of Muscle Research and Cell Motility, Vol: 40, Pages: 169-183, ISSN: 0142-4319

The Popeye domain containing (POPDC) gene family encodes a novel class of membrane-bound cyclic AMP effector proteins. POPDC proteins are abundantly expressed in cardiac and skeletal muscle. Consistent with its predominant expression in striated muscle, Popdc1 and Popdc2 null mutants in mouse and zebrafish develop cardiac arrhythmia and muscular dystrophy. Likewise, mutations in POPDC genes in patients have been associated with cardiac arrhythmia and muscular dystrophy phenotypes. A membrane trafficking function has been identified in this context. POPDC proteins have also been linked to tumour formation. Here, POPDC1 plays a role as a tumour suppressor by limiting c-Myc and WNT signalling. Currently, a common functional link between POPDC’s role in striated muscle and as a tumour suppressor is lacking. We also discuss several alternative working models to better understand POPDC protein function.

Journal article

De Ridder W, Nelson I, Asselbergh B, De Paepe B, Beuvin M, Ben Yaou R, Masson C, Boland A, Deleuze J-F, Maisonobe T, Eymard B, Symoens S, Schindler R, Brand T, Johnson K, Töpf A, Straub V, De Jonghe P, De Bleecker JL, Bonne G, Baets Jet al., 2019, Muscular dystrophy with arrhythmia caused by loss-of-function mutations in BVES, Neurology Genetics, Vol: 5, ISSN: 2376-7839

Objective To study the genetic and phenotypic spectrum of patients harboring recessive mutations in BVES.Methods We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in BVES.Results We identified 4 individuals from 3 families harboring homozygous LOF variants in BVES, the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of BVES through nonsense-mediated decay or through functional changes to the POPDC1 protein.Conclusions We report the identification of homozygous LOF mutations in BVES, causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.

Journal article

Brand T, 2019, Length doesn’t matter. Telomere damage triggers cellular senescence in the ageing heart, EMBO Journal, Vol: 38, ISSN: 0261-4189

Telomere shortening induces cellular senescence in proliferative cells. Yet, it is presently unclear how it is triggered in post‐mitotic cells such as cardiac myocytes. A new study by Anderson et al (2019) reports that during ageing of the heart, cellular senescence develops independently of telomere length, but is evoked by DNA damage, which preferentially accumulates at the telomere. Removal of senescent cells using senolytic drugs ameliorated cardiac hypertrophy and fibrosis and may inform novel approaches to improve the conditions for the ageing heart.

Journal article

Stoyek M, Brand T, Quinn TA, 2018, Role of the intracardiac nervous system in stress-induced arrhythmias with Popdc1 gene mutation, 37th Annual Conference of the North-American-Section (NAS) of the International-Society-for-Heart-Research (ISHR) - Cardiovascular Disease in Vulnerable Populations, Publisher: ELSEVIER SCI LTD, Pages: 107-107, ISSN: 0022-2828

Conference paper

Yu JK, Sarathchandra P, Chester A, Yacoub M, Brand T, Butcher JTet al., 2018, Cardiac regeneration following cryoinjury in the adult zebrafish targets a maturation-specific biomechanical remodeling program, Scientific Reports, Vol: 8, ISSN: 2045-2322

Cardiac regeneration post-injury is a tantalizing feature of many lower vertebrates such as fishes and urodeles, but absent in adult humans. Restoration of pumping function is a key endpoint of cardiac regeneration, but very little is known about the biomechanical remodeling process. Here, we quantify and compare the evolution of cellular composition and mechanical stiffness of the zebrafish ventricular myocardium during maturation and following cryoinjury during regeneration to better understand the dynamics of biomechanical remodeling during these two processes. With increasing age, normal myocardial trabecular density and cardiomyocyte fraction increased, while non-myocyte cell fractions decreased. Cell density remained constant during maturation. Cardiomyocyte sarcomeres shortened to a minimum reached at 7.5 months of age, but lengthened with additional age. Concomitantly, ventricular wall stiffness increased up until 7.5 months before plateauing with additional age. Endothelial, myofibroblast/smooth muscle, and cardiomyocyte cell fractions were disrupted following cryoinjury, but were progressively restored to age-specific natural norms by 35 days post infarct (DPI). Infarcted myocardium stiffened immediately following cryoinjury and was a 100-fold greater than non-infarcted tissue by 3 DPI. By 14 DPI, stiffness of the infarcted myocardium had fallen below that of 0 DPI and had completely normalized by 35 DPI. Interestingly, cardiomyocyte sarcomere length increased until 14 DPI, but subsequently shortened to lengths below age-specific natural norms, indicating recovery from a volume overloaded condition. These observations are consistent with the view that regenerating myocardium requires biomechanical stimulation (e.g. strain) to rescue from a volume overloaded condition. Intriguingly, the biomechanical progression of the infarcted adult myocardial wall mirrors that of normal remodeling during aging. The biomechanical progression of the infarcted myocardium ta

Journal article

Rossi R, Scotton C, Lorenzo M, D'Amico A, Ricci G, Vercelli L, Benedetti S, Bertini E, Mercuri E, Rodolico C, Mongini T, Carboni N, Marrosu G, Chico L, Santoro L, Merlini L, Lattanzi G, Morandi L, Barton PJR, Buchan R, Walsh R, Cook SA, Milting H, Bonne G, Brand T, Ferlini Aet al., 2018, POPDC1 gene mutations screening in laminopathies: possible role as a modifier, 50th European-Society-of-Human-Genetics (ESHG) Conference, Publisher: NATURE PUBLISHING GROUP, Pages: 445-446, ISSN: 1018-4813

Conference paper

Campione M, Brand T, 2018, Special issue: left-right asymmetry and cardiac morphogenesis, Journal of Cardiovascular Development and Disease, Vol: 5, ISSN: 2308-3425

Journal article

Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CSet al., 2018, BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability, Mucosal Immunology, Vol: 11, Pages: 1363-1374, ISSN: 1933-0219

Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves -/- mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves -/- mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves-/- mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.

Journal article

Thompson JJ, Choksi YA, Brown RE, Short SP, Brand T, Lee E, Williams CSet al., 2018, BLOOD VESSEL EPICARDIAL SUBSTANCE (BVES) COORDINATELY REDUCES LRP6 RECEPTOR AND CYTOPLASMIC beta-CATENIN LEVELS TO MODULATE WNT SIGNALING AND INTESTINAL HOMEOSTASIS, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S172-S172, ISSN: 0016-5085

Conference paper

Brand T, 2018, The Popeye domain containing genes and their function as cAMP effector proteins in striated muscle, Journal of Cardiovascular Development and Disease, Vol: 5, ISSN: 2308-3425

The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion of the protein and functions as a cAMP-binding domain. Interestingly, despite the prediction of structural similarity between the Popeye domain and other cAMP binding domains, at the protein sequence level they strongly differ from each other suggesting an independent evolutionary origin of POPDC proteins. Loss-of-function experiments in zebrafish and mouse established an important role of POPDC proteins for cardiac conduction and heart rate adaptation after stress. Loss-of function mutations in patients have been associated with limb-girdle muscular dystrophy and AV-block. These data suggest an important role of these proteins in the maintenance of structure and function of striated muscle cells.

Journal article

Brand T, Schindler, 2017, New kids on the block: The Popeye domain containing (POPDC) protein family acting as a novel class of cAMP effector proteins in striated muscle, Cellular Signalling, Vol: 40, Pages: 156-165, ISSN: 0898-6568

The cyclic 3’,5’-adenosine monophosphate (cAMP) signalling pathway constitutes an ancient signal transduction pathway present in prokaryotes and eukaryotes. Previously, it was thought that in eukaryotes three effector proteins mediate cAMP signalling, namely protein kinase A (PKA), exchange factor directly activated by cAMP (EPAC) and the cyclic-nucleotide gated channels. However, recently a novel family of cAMP effector proteins emerged and was termed the Popeye domain containing (POPDC) family, which consists of three members POPDC1, POPDC2 and POPDC3. POPDC proteins are transmembrane proteins, which are abundantly present in striated and smooth muscle cells. POPDC proteins bind cAMP with high affinity comparable to PKA. Presently, their biochemical activity is poorly understood. However, mutational analysis in animal models as well as the disease phenotype observed in patients carrying missense mutations suggests that POPDC proteins are acting by modulating membrane trafficking of interacting proteins. In this review, we will describe the current knowledge about this gene family and also outline the apparent gaps in our understanding of their role in cAMP signalling and beyond.

Journal article

Poon KL, Liebling M, Kondrychyn I, Brand T, Korzh Vet al., 2016, Development of the cardiac conduction system in zebrafish, Gene Expression Patterns, Vol: 21, Pages: 89-96, ISSN: 1872-7298

The cardiac conduction system (CCS) propagates and coordinates the electrical excitation that originates from the pacemaker cells, throughout the heart, resulting in rhythmic heartbeat. Its defects result in life-threatening arrhythmias and sudden cardiac death. Understanding of the factors involved in the formation and function of the CCS remains incomplete. By transposon assisted transgenesis, we have developed enhancer trap (ET) lines of zebrafish that express fluorescent protein in the pacemaker cells at the sino-atrial node (SAN) and the atrio-ventricular region (AVR), termed CCS transgenics. This expression pattern begins at the stage when the heart undergoes looping morphogenesis at 36 h post fertilization (hpf) and is maintained into adulthood. Using the CCS transgenics, we investigated the effects of perturbation of cardiac function, as simulated by either the absence of endothelium or hemodynamic stimulation, on the cardiac conduction cells, which resulted in abnormal compaction of the SAN. To uncover the identity of the gene represented by the EGFP expression in the CCS transgenics, we mapped the transposon integration sites on the zebrafish genome to positions in close proximity to the gene encoding fibroblast growth homologous factor 2a (fhf2a). Fhf2a is represented by three transcripts, one of which is expressed in the developing heart. These transgenics are useful tools for studies of development of the CCS and cardiac disease.

Journal article

Schindler RFR, Scotton C, French V, Ferlini A, Brand Tet al., 2016, The Popeye Domain Containing Genes and Their Function in Striated Muscle., Journal of cardiovascular development and disease, Vol: 3, ISSN: 2308-3425

The Popeye domain containing (POPDC) genes encode a novel class of cAMP effector proteins, which are abundantly expressed in heart and skeletal muscle. Here, we will review their role in striated muscle as deduced from work in cell and animal models and the recent analysis of patients carrying a missense mutation in POPDC1. Evidence suggests that POPDC proteins control membrane trafficking of interacting proteins. Furthermore, we will discuss the current catalogue of established protein-protein interactions. In recent years, the number of POPDC-interacting proteins has been rising and currently includes ion channels (TREK-1), sarcolemma-associated proteins serving functions in mechanical stability (dystrophin), compartmentalization (caveolin 3), scaffolding (ZO-1), trafficking (NDRG4, VAMP2/3) and repair (dysferlin) or acting as a guanine nucleotide exchange factor for Rho-family GTPases (GEFT). Recent evidence suggests that POPDC proteins might also control the cellular level of the nuclear proto-oncoprotein c-Myc. These data suggest that this family of cAMP-binding proteins probably serves multiple roles in striated muscle.

Journal article

Brand T, 2016, Tbx18 and the generation of a biological pacemaker. Are we there yet?, Journal of Molecular and Cellular Cardiology, Vol: 97, Pages: 263-265, ISSN: 1095-8584

A group of approximately 10,000 cells in the sinoatrial node (SAN), which is located at the entry of the right superior caval vein into the right atrium, is responsible for regular heart beating under different physiological conditions [1]. While the SAN is reliably working for most of our life, in the elderly, sick sinus syndrome (SSS), or sinus node dysfunction (SND) is prevalent [2] and responsible for 30 to 50% of all electronic pacemaker implantations [3]. Moreover, SSS is also often associated with the development of atrial fibrillation [4].

Journal article

Reddy VK, Short SP, Barrett CW, Mittal MK, Keatin CE, Thompson JJ, Harris EI, Revetta F, Bader DM, Brand T, Washington MK, Williams CSet al., 2016, BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt 1 Viability after 2 Radiation, Stem Cells, Vol: 34, Pages: 1626-1636, ISSN: 1549-4918

Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves–/– mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves–/– mice. To examine stem cell function after BVES deletion, we used ex vivo 3D-enteroid cultures. Bves–/– enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar “CBC” and “+4” stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves–/– enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves–/– mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves–/– mice also demonstrated elevations in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis.

Journal article

Rinne S, Ortiz-Bonnin B, Stallmeyer B, Schindler RFR, Kiper AK, Dittmann S, Friedrich C, Zumhagen S, Simrick SL, Gonzalez W, Brand T, Schulze-Bahr E, Decher Net al., 2016, Conduction disorder caused by a mutation in POPDC2, a novel modulator of the cardiac sodium channel SCN5A, Publisher: WILEY-BLACKWELL, ISSN: 1748-1708

Conference paper

Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CW, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CSet al., 2016, BVES regulates c-Myc stability via PP2A and suppresses 1 colitis-induced 2 tumorigenesis, Gut, Vol: 66, Pages: 852-862, ISSN: 1468-3288

Objective Blood vessel epicardial substance (BVES) isa tight junction-associated protein that regulatesepithelial-mesenchymal states and is underexpressed inepithelial malignancy. However, the functional impact ofBVES loss on tumourigenesis is unknown. Here wedefine the in vivo role of BVES in colitis-associatedcancer (CAC), its cellular function and its relevance topatients with IBD.Design We determined BVES promoter methylationstatus using an Infinium HumanMethylation450 arrayscreen of patients with UC with and without CAC. Wealso measured BVES mRNA levels in a tissue microarrayconsisting of normal colons and CAC samples. Bves−/−and wild-type mice (controls) were administeredazoxymethane (AOM) and dextran sodium sulfate (DSS)to induce tumour formation. Last, we used a yeast twohybridscreen to identify BVES interactors and performedmechanistic studies in multiple cell lines to define howBVES reduces c-Myc levels.Results BVES mRNA was reduced in tumours frompatients with CAC via promoter hypermethylation.Importantly, BVES promoter hypermethylation wasconcurrently present in distant non-malignant-appearingmucosa. As seen in human patients, Bves wasunderexpressed in experimental inflammatorycarcinogenesis, and Bves−/− mice had increased tumourmultiplicity and degree of dysplasia after AOM/DSSadministration. Molecular analysis of Bves−/− tumoursrevealed Wnt activation and increased c-Myc levels.Mechanistically, we identified a new signalling pathwaywhereby BVES interacts with PR61α, a proteinphosphatase 2A regulatory subunit, to mediate c-Mycdestruction.Conclusion Loss of BVES promotes inflammatorytumourigenesis through dysregulation of Wnt signallingand the oncogene c-Myc. BVES promoter methylationstatus may serve as a CAC biomarker.

Journal article

Brand T, Schindler RF, 2016, The Popeye domain containing protein family - a novel class of cAMP effectors with important functions in multiple tissues., Progress in Biophysics and Molecular Biology, Vol: 120, Pages: 28-36, ISSN: 1873-1732

Popeye domain containing (Popdc) proteins are a unique family, which combine several different properties and functions in a surprisingly complex fashion. They are expressed in multiple tissues and cell types, present in several subcellular compartments, interact with different classes of proteins, and are associated with a variety of physiological and pathophysiological processes. Moreover, Popdc proteins bind the second messenger cAMP with high affinity and it is thought that they act as a novel class of cAMP effector proteins. Here, we will review the most important findings about the Popdc family, which have been accumulated since its discovery about 15 years ago. We will be focusing on Popdc protein interaction and function in striated muscle tissue. However, as a full picture only emerges if all aspects aretaken into account, we will also describe what is currently known about the role of Popdc proteins in epithelial cells and in various types of cancer, and discuss these findings with regard to their relevance for heart and skeletal muscle.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00581385&limit=30&person=true