Deborah L. Chapman

  • Associate Professor
  • Mouse development

Contact

Office: (412) 624-0774
Lab: (412) 624-0774
101A Life Sciences Annex
Fifth & Ruskin Avenues
Pittsburgh, PA 15260

Figure 1. Errors in somite formation lead to fusions of the ribs (arrows)

Birth defects result from errors made during embryonic development. Normal development involves careful orchestration of multiple events, including changes in gene transcription, cell shape, proliferation, and tissue morphogenesis. Alterations in the developmental program can have dramatic effects on the organism. Sometimes these effects are so drastic that lethality occurs early in the development. Less severe errors may allow the organism to develop, but lead to devastating birth defects. We are interested in how different mesoderm populations arise during development and thus we focus on how mesoderm, produced in the primitive streak, acquires different cell fates and behaviors. We are particularly interested in the specification and development of paraxial mesoderm, which forms somites and ultimately the ribs, vertebrae and skeletal muscle. Improper formation and patterning of paraxial mesoderm can lead to birth defects such as scoliosis, fusions of the ribs (Figure 1) and improper muscles segmentation (Figure 2).

Figure 2. Even spacing of the muscle precursors is altered in embryos when somite patterning is disrupted (right).

During embryogenesis, the primitive streak (PS) generates the paraxial mesoderm (PAM), which undergoes segmentation to form the somites and ultimately the vertebrae, ribs, skeletal muscle and dermis. We are studying the roles that two T-box transcription factors, T and Tbx6, play in mesoderm formation and cell fate decisions. T-box proteins share a similar DNA binding domain, the T-domain, and therefore can bind similar sequences in vitro. T and Tbx6 are both expressed in the PS, but also have unique areas of expression: T in the notochord and Tbx6 in the presomitic PAM. We hypothesize that T is necessary to maintain cells in a PS-like state and enables cells to transition from an epithelial to a mesenchymal cell morphology. T is necessary for continued production of mesoderm and extension of the body axis, while Tbx6 is required to push cells toward a PAM fate.

We use the mouse as a model system to understand how PAM is generated from the PS. The mouse offers a number of advantages, including the ability to routinely inactivate genes and to create transgenic animals that over- or misexpress genes of interest. Because of the close relationship between the mouse and human, it is possible to directly apply things we learn in the mouse to human development. Genetic studies reveal that maintaining the proper levels of T and Tbx6 is critical for normal development and that these factors can compete for binding to downstream targets. We hypothesize that altering the relative levels of T and Tbx6 allows opportunistic binding to the other’s targets and this contributes to the observed phenotypes. We are testing this hypothesis using transgenic approaches to misexpress T and Tbx6 in the embryo. We also use molecular approaches, including luciferase transcriptional assays to examine how T and Tbx6 function alone and together to affect target gene expression and chromatin immunoprecipitations to examine in vivo binding of these factors to target gene enhancers.  These studies will unravel how T and Tbx6 direct cell fate by identifying their target genes and finally testing how target gene expression is altered in T and Tbx6 transgenic embryos.

Sparrow, D. B., McInerney-Leo, A., Gucev, Z. S,

Sparrow, D. B., McInerney-Leo, A., Gucev, Z. S, Gardiner, B., Marshall, M., Leo, P. J., Chapman, D. L., Tasic, V., Shishko, A., Brown, M. A., Duncan, E. L., Dunwoodie, S. L.  Autosomal dominant spondylocostal dysostosis is caused by mutation in Tbx6. Hum Mol Gen 22:1625-1631.

Chalamalasetty, R.B., W.C. Dunty, K.K.  Bi

Chalamalasetty, R.B., W.C. Dunty, K.K.  Biris, M. Iacovino, A. Beisaw, L. Feigenbaum, D.L. Chapman, J.K. Yoon,M. Kyba, T.P. Yamaguchi (2011) The Wnt3a/β-catenin target gene Mesogenin1 controls the segmentation clock by directly activating a Notch signaling program. Nature Communication 2:390.

Wehn, A.K., and D.L. Chapman (2010) Tbx18 and Tbx15 null-like phenotypes in mouse embryos express

Wehn, A.K., and D.L. Chapman (2010) Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm. Dev Biol 347:404-413

Wehn, A.K., P.H. Gallo, and D.L. Chapman (2009) Generation of transgenic mice expressing Cre reco

Wehn, A.K., P.H. Gallo, and D.L. Chapman (2009) Generation of transgenic mice expressing Cre recombinase under the control of the Dll1 mesoderm enhancer element. Genesis 47:309-313

Farkas, D.R., and D.L. Chapman (2009) Kinked tail mutation results in notochord defects in hetero

Farkas, D.R., and D.L. Chapman (2009) Kinked tail mutation results in notochord defects in heterozygotes and distal visceral endoderm defects in homozygotes. Dev Dyn 238:3237-3247

Oginuma, M., Y. Niwa, D.L. Chapman, and Y. Saga (2008) Mesp2 and Tbx6 cooperatively create period

Oginuma, M., Y. Niwa, D.L. Chapman, and Y. Saga (2008) Mesp2 and Tbx6 cooperatively create periodic patterns coupled with the clock machinery during mouse somitogenesis. Development 135:2555-2562

Chapman, D.L. (2006) Paraxial mesoderm signals are required for intermediate mesoderm formation i

Chapman, D.L. (2006) Paraxial mesoderm signals are required for intermediate mesoderm formation in the mouse. Dev. Biol. 295:393-394

White, P.H., D.R. Farkas, and D.L. Chapman (2005) Regulation of Tbx6 expression by Notch

White, P.H., D.R. Farkas, and D.L. Chapman (2005) Regulation of Tbx6 expression by Notch signaling. Genesis 42:61-70

White, P.H., and D.L. Chapman (2005) Dll1 is a downstream target of Tbx6 in the

White, P.H., and D.L. Chapman (2005) Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis 42:193-202

Hogan, K.A., C.A. Ambler, D.L. Chapman, and V.L. Bautch (2004) The neural tube patterns vessels d

Hogan, K.A., C.A. Ambler, D.L. Chapman, and V.L. Bautch (2004) The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development 131:1503-1513

Chapman, D.L., A. Cooper-Morgan, Z. Harrelson, and V.E. Papaioannou (2003) Critical role for

Chapman, D.L., A. Cooper-Morgan, Z. Harrelson, and V.E. Papaioannou (2003) Critical role for Tbx6 in mesoderm specification in the mouse. Mech. Develop. 120:837-847

White, P.H., D.R. Farkas, E.E. McFadden, and D.L. Chapman (2003) Defective somite patterning in m

White, P.H., D.R. Farkas, E.E. McFadden, and D.L. Chapman (2003) Defective somite patterning in mouse embryos with reduced levels of Tbx6. Development 130:1681-1690

Maeda, T., D.L. Chapman, and A.F. Stewart (2002) Mammalian vestigial-like 2, a cofactor of TEF-1

Maeda, T., D.L. Chapman, and A.F. Stewart (2002) Mammalian vestigial-like 2, a cofactor of TEF-1 and MEF2 transcription factors that promotes skeletal muscle differentiation. J. Biol. Chem. 277:48889-48898

Xue, Y., X. Wang, Z. Li, N. Gotoh, D.L. Chapman, and E.Y. Skolnik (2001) Mesodermal patterning de

Xue, Y., X. Wang, Z. Li, N. Gotoh, D.L. Chapman, and E.Y. Skolnik (2001) Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development 128:1559-1572
Dr. Chapman received her Ph.D. in 1993 with Debra Wolgemuth at Columbia University, performed her postdoctoral studies with Virginia Papaioannou at Columbia University, and joined the Department in 1998. Currently, Dr. Chapman is accepting graduate students in her laboratory. Dr. Chapman is accepting undergraduate researchers, and does sponsor students in other laboratories.