Newcastle University

Research Interests

Molecular pathways in cardiac development

This programme of work is a close collaboration between myself and Dr Bill Chaudhry. To date, the research has centred on determining the embryological and molecular mechanisms that underlie cardiac development, focussing on the outflow tract of the heart. These mechanisms are frequently disrupted to result in congenital heart defects. Using a range of mouse mutants, we have established both that proper polarisation of neural crest and second heart field cells is critical for outflow development, and that the non-canonical Wnt, planar cell polarity (PCP), signalling pathway is crucial to this process. This signalling pathway appears to be unique in the extent to which different components have been shown to be essential to outflow tract development; our hypothesis that the PCP pathway signalling is critical has recently been confirmed by several other groups. As we progress with these studies we are beginning to confirm our data in human material.

Experience gained over the past 10 years has placed us in an enviable position with respect to further unravelling the mechanisms underlying outflow tract formation, septation and remodelling. We have a range of mouse models with mutations in different polarity genes and their downstream effectors. Recently (led by Dr Bill Chaudhry), we have also established the zebrafish as a model system for studying the early stages and functional aspects of cardiac development. Together with studies utilising cardiac and embryonic stem cell lines, we thus have a range of tools available for analysing the importance of cell polarity in cardiac development. We have long term collaborations with scientists studying PCP signalling in other developmental systems and with groups studying other aspects of cardiac development.

Our core research activities use transgenic and knock out mice to investigate the role of Wnt signalling pathways in cardiac malformation. We have long standing expertise in these approaches and we are making our own transgenic mice in order to address specific issues. Expertise in mouse cardiac developmental morphology and gene expression are inherent with this approach. Our early studies have focussed on the upstream components of the planar cell polarity pathway (Vangl2, Scrib). This has now expanded to incorporate potential downstream effectors of this pathway, including RhoA, ROCK, Rac and JNK, which regulate key developmental processes such as migration, proliferation and cell death. Thus, we are beginning to understand the complex relationship between gene expression patterns, cell behaviour (e.g. shape, adhesive properties, proliferation, death, differentiation, migration) and the shaping (morphogenesis) of specific cardiac structures. Further unravelling these complex relationships during development, and relating them to regeneration of the damaged adult heart, are our future goals.

Co-workers

Robert Anderson BSc, MD, FRCPath, FESC, FECTS
Visiting Professor
Alina Andras, BSC, PhD
Newcastle Hospitals Trust JRE Research Associate
Michael Baker
Newcastle University
PhD Student
Veronica Boczonadi BSc, MSc
BHF Research Associate
Bill Chaudhry MB BS MRCP PhD
Senior Lecturer in Biophysics and Cardiac Development
Nicholas Child MB BS MRCP
BHF Clinical Research Training Fellowship
Darren Hoyland BSc, PhD
BHF Research Assistant
Tania Papoutsi BSc
BHF PhD Student
Helen Phillips BSc, PhD
Newcastle University Faculty of Medical Sciences Fellow
Hong Jun Rhee BSc, PhD
BHF Research Associate

• Hildreth V, Webb S, Chaudhry B, Peat JD, Phillips HM, Brown N, Anderson RH, Henderson DJ. Left cardiac isomerism in the Sonic hedgehog null mouse. Journal of Anatomy 2009, 214(6), 894-904.
• Bradshaw L, Chaudhry B, Hildreth V, Webb S, Henderson DJ. Dual role for neural crest cells during outflow tract septation in the neural crest-deficient mutant Splotch(2H). Journal of Anatomy 2009, 214(2), 245-257.
• Phillips HM, Hildreth V, Peat JD, Murdoch JN, Kobayashi K, Chaudhry B, Henderson DJ. Non-cell-autonomous roles for the planar cell polarity gene vangl2 in development of the coronary circulation. Circulation Research 2008, 102(5), 615-623.
• Hildreth V, Webb S, Bradshaw L, Brown NA, Anderson RH, Henderson DJ. Cells migrating from the neural crest contribute to the innervation of the venous pole of the heart. Journal of Anatomy 2008, 212(1), 1-11.
• Phillips HM, Rhee HJ, Murdoch JN, Hildreth V, Peat JD, Anderson RH, Copp AJ, Chaudhry B, Henderson DJ. Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization. Circulation Research 2007, 101(2), 137-145.
• Phillips HM, Murdoch JN, Chaudhry B, Copp AJ, Henderson DJ. Vangl2 acts via RhoA signaling to regulate polarized cell movements during development of the proximal outflow tract. Circulation Research 2005, 96(3), 292-299.
• Ioannides AS, Massa V, Ferraro E, Cecconi F, Spitz L, Henderson DJ, Copp AJ. Foregut separation and tracheo-oesophageal malformations: The role of tracheal outgrowth, dorso-ventral patterning and programmed cell death. Developmental Biology 2010, 337(2), 351-262.
• Dhomen N, DaRochaDias S, Hayward R, Ogilvie L, Hedley D, Delmas V, Henderson D, Springer CS, Pritchard C, Larue L, Marais R. Inducible expression of V^600EBraf using tyrosinase-driven Cre recombinase results in embryonic lethality. Pigment Cell & Melanoma Research 2010, 23(1), 112-120.
• Hildreth V, Anderson RH, Henderson DJ. Autonomic Innervation of the Developing Heart: Origins and Function. Clinical Anatomy 2009. DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA: WILEY-LISS, 22(1), 36-46.
• Henderson DJ, Anderson RH. The Development and Structure of the Ventricles in the Human Heart. In: Pediatric Cardiology: Riley Heart Center Symposium on Cardiac Development .2009,Bloomington, Indiana, USA:Springer
• Farooqui-Kabir SR, Diss JKJ, Henderson D, Marber MS, Latchman DS, Budhram-Mahadeo V, Heads RJ. Cardiac expression of Brn-3a and Brn-3b POU transcription factors and regulation of Hsp27 gene expression. Cell Stress and Chaperones 2008, 13(3), 297-312.
• Henderson DJ, Phillips HM, Chaudhry B. Vang-like 2 and noncanonical Wnt signaling in outflow tract development. Trends in Cardiovascular Medicine 2006. , 16(2), 38-45.
• O'Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TVP, Henderson DJ, Nizetic D, Tybulewicz VLJ, Fisher EMC. An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 2005,309 5743 2033-2037.
• Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot M-M, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genetics 2005, 37(10), 1135-1140.
• Gaston-Massuet C, Henderson DJ, Greene NDE, Copp AJ. Zic4, a zinc-finger transcription factor, is expressed in the developing mouse nervous system. Developmental Dynamics 2005, 233(3), 1110-1115.
• Hudson CD, Podesta J, Henderson D, Latchman DS, Budhram-Mahadeo V. Coexpression of Brn-3a POU protein with p53 in a population of neuronal progenitor cells is associated with differentiation and protection against apoptosis. Journal of Neuroscience Research 2004,78 6 803-814.
• Sharma PR, Anderson RH, Copp AJ, Henderson DJ. Spatio-temporal analysis of programmed cell death during mouse cardiac septation. Anatomical Record 2004,277A 2 355-369.
• Murdoch JN, Henderson DJ, Doudney K, Gaston-Massuet C, Phillips HM, Paternotte C, Arkell R, Stanier P, Copp AJ. Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. Human Molecular Genetics 2003. ,12 2 87-98.
• Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B, Copp AJ, Henderson DJ, Spurr N, Stanier P, Fisher EM, Nolan PM, Steel KP, Brown SDM, Gray IC, Murdoch JN. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Current Biology 2003,13 13 1129-1133.
• Ioannides AS, Henderson DJ, Spitz L, Copp AJ. Role for Sonic hedgehog in the development of the trachea and the oesophagus. Journal of Pediatric Surgery 2003,38 1 29-36.
• Ioannides AS, Chaudhry B, Henderson DJ, Spitz L, Copp AJ. Dorsoventral patterning in oesophageal atresia with tracheo-oesophageal fistula: Evidence from a new mouse model. Journal of Pediatric Surgery 2002, 37(2), 185-191.
• Chaudhry B, Burns D, Henderson DJ. Cardiomyocyte aging: swimming against the clock. In: 2nd Congress of the European Society of Cardiology Council on Basic Cardiovascular Science: Frontiers in Cardiovascular Biology. 2012, London, UK: Oxford University Press.
• Bamforth SD, Chaudhry B, Bennett M, Wilson R, Mohun TJ, van Mierop LHS, Henderson DJ, Anderson RH. Clarification of the identity of the mammalian fifth pharyngeal arch artery. Clinical Anatomy 2012. In Press.
• Henderson DJ, Boczonadi V, Humbert P, Chaudhry B. Conditional deletion of Scrib gene in the developing myocardium leads to congenital heart defects. In: 2nd Congress of the European Society of Cardiology Council on Basic Cardiovascular Science: Frontiers in Cardiovascular Biology. 2012, London, UK: Oxford University Press.
• Bell E, Richardson GD, Jahoda C, Phillips H, Henderson D, Owens WA, Hole H. Dermal stem cells can differentiate down an endothelial lineage. Stem Cells and Development 2012. In Press.
• Chaudhry B, Chrystal P, Henderson DJ. Fast Digital Laser Sheet Microscopy: swimaging in 6 dimensions. In: 2nd Congress of the European Society of Cardiology Council on Basic Cardiovascular Science: Frontiers in Cardiovascular Biology. 2012, London, UK: Oxford University Press.
• Phillips HM, Papoutsi T, Soenen H, Ybot-Gonzalez P, Henderson DJ, Chaudhry B. Neural Crest Cell Survival is Dependent on Rho Kinase and is Required for Development of the Mid Face in Mouse Embryos. PLoS One 2012. In Press.
• Anderson RH, Chaudhry B, Mohun TJ, Bamforth SD, Hoyland D, Phillips HM, Webb S, Moorman AF, Brown NA, Henderson DJ. Normal and abnormal development of the intrapericardial arterial trunks in man and mouse. Cardiovascular Research 2012, (epub ahead of print).
• Henderson DJ, Chaudhry B. Getting to the Heart of Planar Cell Polarity Signaling. Birth Defects Research Part A: Clinical and Molecular Teratology 2011, 91(6), 460-467.
• Taylor JM, Saunter CD, Love GD, Girkin JM, Henderson DJ, Chaudhry B. Real-time optical gating for three-dimensional beating heart imaging. Journal of Biomedical Optics 2011, 16, 116021.
• Goodship J, Henderson D. Cardiac development and cardiovascular malformation. In: European Journal of Human Genetics: European Society of Human Genetics European Human Genetics Conference in Conjuction With European Meeting on Psychosocial Aspects of Genetics. 2002, Strasbourg, France: Nature Publishing Group.
• Braybrook C, Lisgo S, Doudney K, Henderson D, Marcano ACB, Strachan T, Patton MA, Villard L, Moore GE, Stanier P, Lindsay S. Craniofacial expression of human and murine TBX22 correlates with the cleft palate and ankyloglossia phenotype observed in CPx patients. Human Molecular Genetics 2002, 11(22), 2793-2804.