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Developmental and Regenerative Biology

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Colin STEWART

Colin Stewart, has been a pioneer in developing many of the techniques that are now widely used in mouse experimental genetics, in establishing protocols for deriving embryonic stem (ES) lines, uniparental ES lines, and for the derivation of the first human ES lines. He was instrumental in identifying the cytokine LIF as being crucial to sustaining stem cell pluripotency (Nature 1988). Subsequently he showed that LIF and its signalling pathway is critical to regulating uterine receptivity for embryo implantation in mammals (Nature 1993). He developed numerous mouse models of congenital diseases, particularly those arising from defective genomic imprinting e.g. Prader-Willi. Over the last decade his interests have centered on the laminopathies, a heterogeneous collection of diseases all arising from mutations in the LaminA gene. He collaborated with Nicolas Lévy, in being the first to show that mutations in the LMNA gene cause progeria (Science 2003), and to make mouse models of many of the laminopathies, including progeria. He also developed the first iPSCs lines derived from patient fibroblasts in establishing an in vitro model for Progeria (HGPS). Currently, he is a founding partner of Daedalus Therapeutics that is developing new treatments to ameliorate cardiomyopathies and vascular disease.

My research centres on the analysis of the functional architecture of the cell’s nucleus, in particular the nuclear lamina and envelope, and how they regulate mammalian development, epigenetics and, postnatal tissue integrity and ageing.  My lab has a particular interest in diseases arising from disruption in the organization and function of the nuclear lamina and envelope.  These diseases, of which at least 30 have been described, are quite rare but provide novel insights into some of the more widespread major issues of 21st century health care, particularly obesity, aging, stem cell maintenance, muscle regeneration and cardiovascular disease.

The study of such rare diseases also offers an entry to the understanding of what I refer to as “supra-epigenetics”, namely how the structural organization of the cell’s nucleus is critical to regulating chromatin organization, nucleus-cytoskeleton interactions, telomere maintenance and signalling pathways.  More recently, together with my long-term colleague Brian Burke, we are developing a novel range of and approaches to treating cardiovascular diseases utilizing Adeno Associated Viral Vectors (AAV) to deliver therapeutics aimed at disrupting the nuclear LINC complexes.

In addition, I partner with L’Oreal at looking at mechanisms of skin ageing and I oversee the mouse knock-out core where we have generated ~80 lines of mutant mice.

 

Group Members

 Senior Research Fellows  Alexandre Chojnowski 
 Research Fellows  Loo Tsui Han

 Hendrikje Werner
   Chai Jinfen, Ruth
   Tan Meng Kwang, Marcus
   Wong Xianrong
Research Officers  Rafidah Abdul Mutalif
   Navasankari Raju

KOre - Knock-Out resource (Link)

 Senior Research Fellows  Wong Sook Miin, Esther
 Research Officers  Leong Ei Leen
   Nguyen Thi Minh

Mzoughi S, Zhang J, Hequet D, Teo SX, Fang H, Xing QR, Bezzi M, Seah MKY, Ong SLM, Shin EM, Wollmann H, Wong ESM, Al-Haddawi M, Stewart CL, Tergaonkar V, Loh YH, Dunn NR, Messerschmidt DM, Guccione E. PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling. Nat Genet. 2017 Sep;49(9):1354-1363. doi: 10.1038/ng.3922. Link
Cheng J, Rosario G, Cohen TV, Hu J, Stewart CL. Tissue-Specific Ablation of the LIF Receptor in the Murine Uterine Epithelium Results in Implantation Failure. Endocrinology. 2017 Jun 1;158(6):1916-1928. doi: 10.1210/en.2017-00103 Link
Kwan R, Brady GF, Brzozowski M, Weerasinghe SV, Martin H, Park MJ, Brunt MJ, Menon RK, Tong X, Yin L, Stewart CL, Omary MB. Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. Cell Mol Gastroenterol Hepatol. 2017 Jul 6;4(3):365-383. doi: 10.1016/j.jcmgh.2017.06.005 Link
Traber KE, Symer EM, Allen E, Kim Y, Hilliard KL, Wasserman GA, Stewart CL, Jones MR, Mizgerd JP, Quinton LJ. Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol. 2017 Sep 1;313(3):L548-L558. doi: 10.1152/ajplung.00482.2016 Link
Wang AS, Kozlov SV, Stewart CL, Horn HF. Tissue specific loss of A-type lamins in the gastrointestinal epithelium can enhance polyp size. Differentiation. 2015 Jan 8. pii: S0301-4681(14)00097-8. doi: 10.1016/j.diff.2014.12.002. [Epub ahead of print] PubMed PMID: 25578479. Link
Chojnowski A, Ong PF, Wong ESM, Lim JSY, Mutalif RA, Navasankari R, Dutta B, Yang H, Liow YY, Sze SK, Boudier T, Wright GD, Colman A, Burke B, Stewart CL, Dreesen O. Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria. eLife. 2015 Aug 27; 10.7554/eLife.07759 Link
Calvi A, Wong AS, Wright G, Wong ES, Han Loo T, Stewart CL, Burke B. SUN4 is essential for nuclear remodeling during mammalian spermiogenesis. Dev Biol. 2015 Sep 25. pii: S0012-1606(15)30200-1. doi: 10.1016/j.ydbio.2015.09.010. PubMed PMID: 26417726. Link
Rosario GX, Hondo E, Jeong JW, Mutalif R, Ye X, Yee LX, Stewart CL. The LIF-mediated molecular signature regulating murine embryo implantation. Biol Reprod. 2014 Sep;91(3):66. doi: 10.1095/biolreprod.114.118513. Epub 2014 Jul 16. PubMed PMID: 25031358. Link
Stewart CL, Burke B. The missing LINC: a mammalian KASH-domain protein coupling meiotic chromosomes to the cytoskeleton. Nucleus. 2014 Jan-Feb;5(1):3-10. doi: 10.4161/nucl.27819. Epub 2014 Jan 23. PubMed PMID: 24637401; PubMed Central PMCID: PMC4028352. Link
Horn HF, Kim DI, Wright GD, Wong ES, Stewart CL, Burke B, Roux KJ. A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. J Cell Biol. 2013 Sep 30;202(7):1023-39. doi: 10.1083/jcb.201304004. Epub 2013 Sep 23.PubMed PMID: 24062341; PubMed Central PMCID: PMC3787381. Link
Dreesen O, Chojnowski A, Ong PF, Zhao TY, Common JE, Lunny D, Lane EB, Lee SJ,Vardy LA, Stewart CL, Colman A. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J Cell Biol. 2013 Mar 4;200(5):605-17. doi: 10.1083/jcb.201206121. Epub 2013 Feb 25. PubMed PMID: 23439683; PubMed Central PMCID: PMC3587829. Link
Solovei I, Wang AS, Thanisch K, Schmidt CS, Krebs S, Zwerger M, Cohen TV, Devys D, Foisner R, Peichl L, Herrmann H, Blum H, Engelkamp D, Stewart CL, Leonhardt H, Joffe B. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell. 2013 Jan 31;152(3):584-98. doi: 10.1016/j.cell.2013.01.009. PubMed PMID: 23374351. Link
Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O, Friedman LM, Roux KJ, Kozlov S, Jeang KT, Frydman M, Burke B, Stewart CL, Avraham KB. The LINC complex is essential for hearing. J Clin Invest. 2013 Feb;123(2):740-50. doi: 10.1172/JCI66911. Epub 2013 Jan 25. PubMed PMID: 23348741; PubMed Central PMCID: PMC3561815. Link
Burke, B., and Stewart C. L. (2012) The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol. 14 (1): 13-24.
Chen, K., et al. (2012) Accumulation of the Inner Nuclear Envelope Protein Sun1 is Pathogenic in Progeric and Dystrophic Laminopathies. Cell 149: 565-577.
Zhang J., et al (2011) A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8:31-45.
Hernandez L., et al (2010) Functional coupling between the extracellular matrix and nuclear lamina by Wnt signalling in Progeria. Dev Cell 19: 413-25.
Gonzalez-Suarez I., et al. (2009) Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. 28: 2414-27.
Roux K.J, et al. (2009) Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization. Proc Natl Acad Sci USA; 106 (7): 2194-9.
Naetar N., et al. (2008) Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation. Nat Cell Biol.10: 1341-8.
Cohen T.V, et al. (2008) The Lamin B Receptor under transcriptional control of C/EBP-epsilon is required for morphological but not functional maturation of neutrophils. Hum Mol Genet. 17:2921-33.
Stewart C.L, et al. (2007) Blurring the boundary: the nuclear envelope extends its reach. Science 318:1408-12.
Kozlov, S.V, et al. (2007) Magel2, an imprinted gene in the Prader-Willi Syndrome region is required for normal circadian output. Nat Genet 39: 1266-1272.
Cohen, T.V., et al. (2007) The nuclear envelope protein Man1 regulates TGFβ signalling in the embryonic yolk-sac. Development 134: 1385-1395.