Molecular Mechanisms in Development
Dr Cheung, Martin Chi Hang (張知恆)
Research Assistant Professor, Department of Biochemistry
BSc (CUHK); PhD (Nottingham University)
- Email: firstname.lastname@example.org
- Tel: +852 28199541 (Office); +852-28199851 (Lab)
- Office: L3-78, Laboratory Block, 21 Sassoon Road, Hong Kong
Postgraduate Research Projects Available:
- Transcriptional control of neural crest formation and delamination
- Investigating the role of SoxE genes in tumor metastatsis
- Dissecting the molecular mechanism of osteo-chondroprogenitors formation
My long-standing research interest has been focusing on dissecting the cell intrinsic pathway of neural crest formation and delamination using chick and mouse embryos as the experimental systems.
Neural crest cells (NCCs) belong to a population of proliferative, migratory and multipotent progenitor cells found in all vertebrate embryos. Prospective NCCs arise from the dorsal neural fold at the border between the neural plate and non-neural ectoderm, with a neuroepithelial character; later, they transform into actively motile mesenchymal cells in a process called epithelial-mesenchymal transition (EMT). These cells then delaminate from the dorsal neuroepithelium and migrate extensively throughout the embryo to form various cell types. The intrinsic determinants that direct NC formation and EMT are not well defined.
Group E Sox genes (Sox8, Sox9 and Sox10) belonging to high-mobility-group (HMG) transcription factors are expressed in prospective NCCs and Sox9 expression precedes expression of a number of premigratory NC markers. Our overexpression analysis in chick embryos by electroporation demonstrated that the proper specification of the trunk NCCs requires concomitant activity of Sox9, Snail2 and FoxD3. Forced expression of Sox9 promotes NC-like differentiation and its survival but requires Snail2 activity to trigger NC delamination with EMT characteristics in which cells undergo dramatic changes in cell shape, loss of epithelial conformation and the acquisition of cell motility. Moreover, FoxD3 not only promotes NC-like differentiation process similar to Sox9 but also regulates the expression of cell-cell adhesion molecules required for NC migration. Together, the data suggest a combinatorial role of different families of transcription factors expressed by prospective NCCs, which control and coordinate the NC induction, EMT and survival.
These findings open up a number of potentially interesting avenues that we will pursue:
- Using microarray approach, we aim to identify potential downstream candidates of Sox9 and Sox9/Snail2 mediating the process of NC induction and EMT respectively.
- Using transgenic approach in mice, we aim to identify the regulatory regions involved in directing NC expression of Sox9.
- Using biochemical and in ovo electroporation approaches, we aim to understand the impact of post-translational modifications (phosphorylation and Sumoylation) on Sox9 protein activities in the process of NC induction and EMT.
- The shared features of EMT between NC development and tumor metastatsis prompt us to investigate whether SoxE proteins also play a role in mediating the EMT for an epithelial tumor cell to progress from noninvasive to invasive state.
Being part of the research team of the Area of Excellence (AoE) in Developmental Genetics and Skeletal Research, my research is also focused on investigating the molecular mechanism of how osteo-chondroprogenitors is generated in order to develop efficient protocols for directing stem cells or somatic cells differentiation into these progenitors for therapeutic purposes.
Bone and cartilage are major tissues in the vertebrate skeletal system and their progenitors, osteoblasts and chondrocytes, are thought to differentiate from a common mesenchymal precursor, the osteo-chondroprogenitor. These progenitors then undergo both endochondral ossification in limb skeleton where mesenchyme cells condense to form a cartilaginous template which is eventually replaced by bone; and intramembranous ossification taking place in most part of the skull where a condensed mesenchymal cell layer differentiate into osteoblast. A recent study demonstrated that all osteo-chondroprogenitors are derived from Sox9-expressing mesenchymal progenitor cell during limb development and several signaling molecules appear to act in concert to specific these progenitors for endochondral or intramembranous ossification. However, little is known about the underlying mechanism of how extracellular signals regulate Sox9 expression in these progenitor cells. Understanding the regulatory mechanism of osteo-chondroprogenitor formation would allow us to develop efficient protocol to direct the fate of stem cells or somatic cells into osteo-chondrogenic lineages for regenerative tissue engineering.
Figure showing Sox9 protein expression (red) in the delaminating neural crest cells which is also marked by HNK-1 expression (green)
Publications, Achievements, and Grants:
- Liu, A.J.J., Wu, M.H., Yan, C., Chau, K.H.B., So, H., Ng, A., Chan, A., Cheah, K.S.E., Briscoe, J. and Cheung, M.* (2013) Phosphorylation of Sox9 is required for neural crest delamination and is regulated downstream of BMP and canonical Wnt signaling. Proc Natl Acad Sci USA 110 (8): 2882-2887. (*corresponding author)
- Scott, C.E., Wynn, S.L., Sesay, A., Cruz, C., Cheung, M., Gomez Gaviro, M.V., Booth, S., Gao, B., Cheah, K.S., Lovell-Badge, R. and Briscoe, J. (2010) Sox9 induces and maintains neural stem cells. Nat Neurosci 13 (10): 1181-1190.
- Tsang, Y.K., Cheung, M., Chan, D. and Cheah, K.S. (2009) The Developmental Roles of the extracellular matrix: beyond structure to regulation. Cell Tissue Res 339(1): 93-110.
- Bao, B., Hu, J., Stricker, S., Cheung, M., Ma, G., Law, K.F., Witte, F., Briscoe, J., Mundlos, S., He, L., Cheah, K.S. and Chan, D. (2009) Mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 458: 1196-1204.
- Cheung, M. and Chan, D. (2008) “Principles of Developmental Genetics” JAMA 299(11): 1366-1367 (* equal contribution) - Book Review
- Cheung, M., Chaboissier, M-C., Mynett, A., Hirst, E., Schedl, A. and Briscoe. J. (2005) The transcriptional control of trunk neural crest induction, survival and delamination. Dev Cell 8: 179-192.
- Cheung, M. and Briscoe, J. (2003) Neural crest development is regulated by the transcription factor Sox9. Development 130: 5681-5693.
- Lee, C.J., Chan, W.I., Cheung, M., Cheng, Y.C., Appleby, V.J., Orme, A.T. and Scotting, P.J. (2002) CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. Mol Brain Res 106: 151-156.
- Abu-Elmagd, M., Ishii, Y., Cheung, M., Rex, M., Le Rouëdec, D. and Scotting, P.J. (2001) cSox3 expression and neurogenesis in the epibranchial placodes. Dev Biol 237: 258-269.
- Cheng, Y.C., Cheung, M., Abu-Elmagd, M., Orme, A. and Scotting, P.J. (2000) Chick Sox10, a transcription factor expressed in both early neural crest cells and central nervous system. Dev Brain Res 121: 233-243.
- Cheung, M., Abu-Elmagd, M., Clevers, H. and Scotting, P.J. (2000) Roles of Sox4 in central nervous system development. Mol Brain Res 79: 180-191.