lung development, cardiac development, vascular development, Wnt signaling, regulation of gene transcription, GATA factors, forkhead factors
lung, vascular, heart, GATA, forkhead, Wnt.
Description of Research
Our lab is focused on the molecular pathways involved in the formation and differentiation of the mammalian lung and cardiovascular system. In the mouse, the lung develops from the primitive foregut endoderm at approximately E9.5 of gestation. Budding endoderm from the foregut differentiates into primitive pulmonary epithelium and which is surrounded by splanchnic mesoderm, which forms the lung mesenchyme. As development proceeds, cell specific programs are initiated along a proximal-distal axis such that epithelial cell lineages are distinct in the proximal versus distal regions of the lung by mid to late gestation (E15.5-E17.5). This patterning is similar to that observed in other branching organs including the kidney and mammary gland.
The cardiovascular system begins to develop at E7.5 when the precardiac mesoderm initially begins to differentiate into definitive cardiac cell lineages. Further development results into the four-chambered heart and the complex vascular plexus required for survival past early to mid gestation. Several cell types contribute to the morphogenesis of the cardiovascular system including mesodermally derived cardiac and vascular smooth musclemyocytes, neural crest derived vascular smooth muscle, and endothelium. Of these cell types, the development and differentiation of vascular smooth muscle remains relatively unexplored. We have identified several transcription factors and signaling molecules that are important for lung and cardiovascular development including the zinc finger transcription factor GATA-6, Foxp1/2/4, and the Wnt signal transduction pathway. We utilize in vivo mouse and zebrafish models to study the role of these factors during development. This includes the generation and analysis of transgenic and knock-out mice and morpholino knock-down strategies in fish. Our overall goal is to elucidate the underlying causes and mechanisms that lead to both neonatal and adult cardiopulmonary disease.
General topics include:
- role of Wnt signaling in vascular and airway development
- fate mapping of vascular and epithelial stem/progenitor cells in the lung
- explore redundancy of Foxp1/2/4 in lung and cardiovascular development
- characterize novel Foxp1/2/4 interacting proteins and their role in chromatin remodeling
Shanru Li-Research Associate,
Yu-Zhen Zhang-Research Associate,
Ann Chokas-postdoctoral fellow,
Ethan David Cohen-postdoctoral fellow,
Ying Tian-postdoctoral fellow,
Karthika Muthukumaraswamy-Lab manager/Research Specialist,
Zhishan Wang-Research Specialist,
Ashley Goss- Graduate Student.
Lepore, J.J., Cappola, T.P., Mericko, P.A., Morrisey, E.E., and Parmacek, M. S. : GATA-6 regulates genes promoting synthetic functions in vascular smooth muscle cells. Arteriorsclerosis Thrombosis and Vascular Biology 25(2): 309-14, February 2005.
Zhao,R., Watt, A.J., Li,J., Luebke-Wheeler, J., Morrisey, E.E., and Duncan, S.A.: GATA6 is essential for embryonic development of the liver but dispensable for early heart development. Molecular and Cellular Biology 25(7): 2622-2631, April 2005.
Lepore, J.J., Cheng, L., Lu, M.M., Mericko, P.A., Morrisey, E.E., and Parmacek, M.S.: High efficiency somatic mutagenesis in smooth muscle cells and cardiac myocytes in SM22α-cre transgenic mice. Genesis 41(4): 179-184, April 2005.
Shu,W., Cho,J., Jiang,Y., Zhang,M., Haroutunian,V., Weisz,D., Perl,D., Morrisey, E.E*., and Buxbaum, J. D*: Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proceedings of the National Academy of Sciences 102: 9643-9648, 2005 Notes: * these laboratories contributed equally to these studies.
Shu,W., Wang,Z., Lu, M.M., Whitsett, J.A., Millar, S.E., and Morrisey, E.E. : Wnt/β-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Developmental Biology 283(1): 226-239, July 2005.
Wang,Z., Shu,W., Lu, M.M., Millar S.E., and Morrisey, E.E. : Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5. Molecular and Cellular Biology 25(12): 5022-5030, June 2005.
Rath,N., Wang,Z., Lu, M.M., and Morrisey, E.E. : LMCD1/dyxin is a novel transcriptional co-factor that restricts GATA6 function by inhibiting DNA binding. Molecular and Cellular Biology 25(20): 8864-8873, October 2005.
Lobov,I.B., Rao,S., Carroll,T.J., Vallance,J.E., Ito,M., Ondr,J.K., Kurup, S., Glass,D.A., Pate,M.S., Shu,W., Morrisey,E.E., McMahon,A.P., Karsenty, G. and Lang,R.A. : WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437(7057): 417-421, September 2005.
Li, S., Weidenfeld, J., and Morrisey, E.E. : Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic proteins interactions. Molecular and Cellular Biology 24(2): 809-822, January 2004.
Haesler, S., Wada, K., Nshdejan,A., Morrisey,E.E., Lints, E.K.T., Jarvis, E.D., and Scharff, C. : Foxp2 expression in avian vocal learners and non-learners. Journal of Neuroscience 24(13): 3164-3175, March 2004.
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Last updated: 10/19/2016
The Trustees of the University of Pennsylvania