Philip INGHAM / Tom CARNEY    
                       
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  Philip INGHAM  
  Lab Location: #8-03

email:
pingham@imcb.a-star.edu.sg
tel:65869736
 
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  Tom CARNEY  
  Lab Location: #8-02B

email:
tcarney@imcb.a-star.edu.sg
tel:65869732
 
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  Key Publications  
 

Philip Ingham's publications

Maurya, AK. Ben, J, Zhao, Z. Lee, R.  Niah, W. Ng, ASM. Elworthy, S. van Eeden, FJ. and Ingham, PW. (2013) Regulation of Gli transcription factor activity by Kif7 in the zebrafish embryo.
PLoS Genet. 9(12):e1003955.

Hynes NE, Ingham PW, Lim WA, Marshall CJ, Massagué J, Pawson T. (2013)
Signalling change: signal transduction through the decades
Nat Rev Mol Cell Biol. 14(6):393-8.

Maurya AK, Tan H, Souren M, Wang X, Wittbrodt J, Ingham PW. (2011)
Integration of Hedgehog and BMP signalling by the engrailed2a gene in the zebrafish myotome.
Development. 138(4):755-65.
http://dev.biologists.org/ content/138/4/755.long

Ingham PW, Nakano Y and Seger C (2011).
Mechanisms and functions of Hedgehog signalling across the Metazoa.
Nature Rev Genetics, 12(6):393-406.

von Hofsten J, Elworthy S, Gilchrist MJ, Smith JC, Wardle FC, Ingham PW (2008)
Prdm1- and Sox6-mediated transcriptional repression specifies muscle fibre type in the zebrafish embryo
EMBO Reports 9(7): 683-89

Shivdasani, A.A. and Ingham, P.W. (2003)
Regulation of stem cell maintenance and transit amplifying cell proliferation by TGF-beta signaling in Drosophila spermatogenesis.
Current Biology 13:2065-72

Wolff, C, Roy, S. and Ingham, P.W. (2003)
Multiple muscle cell identities induced by distinct levels and timing of Hedgehog activity in the zebrafish embryo.
Current Biology 13:1169-81

Ingham PW, McMahon AP. (2001)
Hedgehog signaling in animal development: paradigms and principles.
Genes Dev. 15(23):3059-87.

van den Heuvel M, Ingham PW. (1996)
Smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.
Nature 382(6591):547-51.

Currie PD, Ingham PW. (1996)
Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish.
Nature 382(6590):452-5.

Krauss S, Concordet JP, Ingham PW. (1993)
A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos.
Cell 75(7):1431-44.

Tom Carney's publications

Lee RT, Asharani PV, Carney TJ (2014)
Basal keratinocytes contribute to all strata of the adult zebrafish epidermis.
PLoS One 9: e84858.

Lee RT, Thiery JP, Carney TJ (2013)
Dermal fin rays and scales derive from mesoderm, not neural crest.
Curr Biol 23: R336-337.

Lee RT, Knapik EW, Thiery JP, Carney TJ (2013)
An exclusively mesodermal origin of fin mesenchyme demonstrates that zebrafish trunk neural crest does not generate ectomesenchyme. Development 140: 2923-2932.

Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, Yigit G, Pohl E, Becker J, Frommolt P, Sonntag C, Altmuller J, Zimmermann K, Greenspan DS, Akarsu NA, Netzer C, Schonau E, Wirth R, Hammerschmidt M, Nurnberg P, Wollnik B, Carney TJ (2012) Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish.
Am J Hum Genet
90: 661-674.

Carney TJ, Feitosa NM, Sonntag C, Slanchev K, Kluger J, Kiyozumi D, Gebauer JM, Coffin Talbot J, Kimmel CB, Sekiguchi K, Wagener R, Schwarz H, Ingham PW, Hammerschmidt M (2010)
Genetic analysis of fin development in zebrafish identifies Furin and Hemicentin1 as potential novel Fraser Syndrome disease genes.
PLoS Genetics 6: e1000907.

Slanchev K, Carney TJ, Stemmler MP, Koschorz B, Amsterdam A, Schwarz H, Hammerschmidt M (2009)
The epithelial cell adhesion molecule EpCAM is required for epithelial morphogenesis and integrity during zebrafish epiboly and skin development. PLoS Genetics 5: e1000563.

Carney TJ, von der Hardt S, Sonntag C, Amsterdam A, Topczewski J, Hopkins N, Hammerschmidt M (2007) Inactivation of serine protease Matriptase1a by its inhibitor Hai1 is required for epithelial integrity of the zebrafish epidermis.
Development 134: 3461-3471.

 
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  Philip INGHAM


Philip Ingham FRS received his D. Phil from Sussex University, UK, after reading Philosophy, Theology and Genetics at Cambridge University. He was a post-doctoral fellow at the CNRS LGME in Strasbourg, France and at the ICRF Mill Hill laboratories in London, England, before becoming a junior Group Leader at the MRC Laboratory of Molecular Biology in Cambridge. In 1986 he was appointed Research Scientist at the ICRF Developmental Biology Unit in Oxford and became a Principal Scientist at the ICRF Lincoln's Inn Fields Laboratories in London in 1994. In 1996 was appointed Professor of Developmental Genetics at the University of Sheffield, UK where he established the MRC Centre for Developmental and Biomedical Genetics, of which he is currently Director. He was Chairman of the British Society for Developmental Biology from 1999 to 2004 and has served on the editorial boards of a number of leading journals including Developmental Cell, Genes & Development, Current Biology and the EMBO Journal. He was elected a member of EMBO in 1995, a Fellow of the Academy of Medical Sciences in 2001 a Fellow of the Royal Society in 2002 and an Honorary Fellow of the Royal College of Physicians in 2007. He received the Medal of the Genetics Society of Great Britain in 2005.

 

  Tom CARNEY


Tom Carney graduated from the Genetics Department at the University of Adelaide before embarking on a PhD in zebrafish developmental biology in the laboratory of Robert Kelsh at the University of Bath, UK, studying specification of neural crest derivatives. He continued zebrafish research as a postdoctoral fellow with Matthias Hammerschmidt at the Max Planck Institute for Immunobiology in Freiburg, Germany from 2004. Here, he analysed a number of epidermal mutants, elucidating the role of novel extracellular matrix proteins and serine proteases in development. Tom moved to Singapore in October 2008. He is currently co-Principal Investigator with Prof Ingham in the Developmental and Biomedical Genetics Laboratory. His current research focuses on proteolytic pathways in development and disease.

 

     
  Research in the Ingham Laboratory
 


The powerful genetics and exquisite embryology of the zebrafish has established this organism as an outstanding non-mammalian model for the analysis of vertebrate embryonic development. The unique experimental advantages of the zebrafish include the optical clarity, accessibility and rapid development of its embryo, the availability of large collections of mutations disrupting essential genes and the relative simplicity of its organ systems. Despite this simplicity, the zebrafish shares many fundamental similarities with other vertebrates; for instance, the patterning of the neural tube, the control of neural and glial differentiation, the specification and differentiation of blood cell lineages and the development and function of the heart. Thus insights from studies in zebrafish can readily be applied directly to higher vertebrates, including humans.

Our research group uses the zebrafish Danio rerio as a model system to study a number of related processes in vertebrate development. In particular, we focus on the role of signaling pathways and the gene regulatory networks (GRNs) that they control. We also use the fish to model human disease related processes such as the inflammatory response and tumour angiogenesis and metastasis. Our approach is based on understanding complex biological processes in the context of the whole organism: we use a range of techniques that take advantage of the properties of the zebrafish, including in vivo imaging, transgenesis, antisense mediated gene knockdown, Zinc finger nuclease mediated targeted gene knock-out, Tandem Affinity Purification of protein complexes and Chromatin Immuno Precipitation (ChIP).

 

  Hedgehog Signalling
 


Hedgehog (Hh) proteins constitute one of the handful of families of signaling molecules that regulate animal development. Dysfunction of the Hh signaling pathway results in severe developmental defects and is associated with a number of different types of tumour in human. Although the pathway has been highly conserved through evolution, there are some important differences, particularly between Drosophila, the species in which most is know about the mechanism of Hh signaling, and vertebrates. We are using a combination of genetic and proteomic analyses in the zebrafish to probe both the conservation and divergence of Hh pathway mechanisms and function.

Collaborators: Dr. F van Eeden, University of Sheffield, UK; Dr. W. Blackstock, IMCB

 

Figure 1: Somitic cells in a zebrafish embryo showing accumulation of GFP tagged Gli2 protein at the tips of primary cilia in response to Hedgehog pathway activation (from Kim et al., 2010).

 

  Myogenic Gene Regulatory Networks (GRNs)
 


Skeletal muscle is a major component of vertebrate anatomy, making up around 50% of the body mass of a human and around 80% of that of a fish. A number of transcription factors are known to commit cells to the myogenic lineage, but how myoblasts differentiate into different types of muscle is rather less well understood. We are use a combination of genetics, in vivo promoter analysis and ChIP to elucidate the GRNs that underlie the commitment and differentiation of myoblasts into different muscle cell type. A particular focus of our research is the transcription factor Sox6, which plays a key role in regulating the choice between slow-twitch and fast-twitch fibre type. We are studying the targets of this protein and also the transcriptional and post-transcriptional regulation of the gene that it is encoded by.

Collaborators: Prof. Y-J Ruan, Genome Institute of Singapore; Dr. J. von Hofsten, Umea University, Sweden; Dr. V. Cunliffe, University of Sheffield; Dr. N. Hagiwara, Univeristy of California, Davis

 

Figure 2: Cross section through the trunk region of a 6 day old zebrafish embryo showing the superficial slow twitch muscle fibres (labeled red) and expression of a sox6:gfp reporter gene (green) restricted to the fast twitch muscle fibres.

 

  Haematopoietic Stem Cell Factors
 


All vertebrates have primitive and definitive waves of hematopoiesis, the latter process producing the self-renewing pluripotent hematopoietic stem cells (HSCs). Elucidating the GRNs that underlie the formation and maintenance of HSCs will facilitate the generation and manipulation of these cells for therapeutic use and at the same time lead to a better understanding of the molecular pathways underlying leukemia. Many of the transcription factor known to play a critical role during mammalian hematopoiesis have analogous roles in zebrafish, making the fish an attractive model system for studying HSC biology. We are conducting a large-scale functional screen of candidate HSC regulators, using antisense oligonucleotide mediated gene knockdown.

Collaborators: Prof. R Patient, University of Oxford, Prof T Enver, University College London

 

Figure 3: Depletion of Haematopoietic Stem Cells (HSCs) in the floor of the dorsal aorta, reveled by ISH for the c-myb transcript, following Morpholino mediated knockdown of a candidate HSC regulatory gene.

 

  Disease Models
 


The zebrafish is increasingly being used to model human disease-related processes, its easily accessible and transparent embryos and relatively simple and low-cost husbandry making it an attractive alternative to the expensive conventional mammalian model organisms. We have developed paradigms for the analysis of two different pathological conditions: first, using a transgenic line expressing GFP under the control of a neutrophil specific promoter, we study neutrophil behaviour in response to trauma or chronic inflammatory stimuli. In a second line of research, we have developed a tumour xenograft model to study the interaction of tumour cells with the vascular system and the dispersal of cells away from the primary tumour site.

Collaborators: Dr. S Renshaw, Prof. M. Whyte, University of Sheffield; Prof. Y Cao, Karolinska Institute, Stockholm

 

Figure 4: A cluster of implanted murine fibrosarcoma tumour cells (red) in a three day old fli1:gfp transgenic zebrafish embryo showing recruitment of blood vessels (green) by the xenograft.

 

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