The goal of the work in this proposal is a characterization of the Msx1 gene in the mouse. Msx1 encodes a homeodomain protein which when deleted causes cranial facial defects in mice. During the past funding period, Abate identified a DNA binding consensus for Msx1 and produced convincing data that the gene functions as a repressor of transcription in vitro. Moreover, she showed that this repressor activity does not require Msx=s binding to its target DNA, although it does require an intact Msx homeodomain. Abate argues that Msx's transcriptional specificity reflects an interaction with other proteins in a large Msx complex and has identified several possible candidates. The future analysis of these interacting proteins and the resultant specificity of the complex provide the basis for the proposed experiments in this application. To evaluate the in vivo significance of newly identified potential candidates she has established cell lines in which Msx can be induced under TET control and its effects assayed by activation of MyoD. As a first step in developing a biologically relevant assay for Msx function, she has used the Tabin retroviral expression systems to overexpress Msx in the Chick limb. Overexpression at stage 10 causes wide spread defects in limb development. More useful for the present proposal is her observation that injection at stage 17 blocks differentiation of feather follicles. Abate proposes to develop this overexpression phenotype as a quantitative assay for function.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029446-09
Application #
6182106
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Henken, Deborah B
Project Start
1992-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
9
Fiscal Year
2000
Total Cost
$244,152
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Wang, Jingqiang; Abate-Shen, Cory (2012) The MSX1 homeoprotein recruits G9a methyltransferase to repressed target genes in myoblast cells. PLoS One 7:e37647
Wang, Jingqiang; Abate-Shen, Cory (2012) Transcriptional repression by the Msx1 homeoprotein is associated with global redistribution of the H3K27me3 repressive mark to the nuclear periphery. Nucleus 3:155-61
Wang, Jingqiang; Kumar, Roshan M; Biggs, Vanessa J et al. (2011) The Msx1 Homeoprotein Recruits Polycomb to the Nuclear Periphery during Development. Dev Cell 21:575-88
Lee, Hansol; Quinn, John C; Prasanth, Kannanganattu V et al. (2006) PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Genes Dev 20:784-94
Lee, Hansol; Habas, Raymond; Abate-Shen, Cory (2004) MSX1 cooperates with histone H1b for inhibition of transcription and myogenesis. Science 304:1675-8
Bendall, Andrew J; Hu, Gezhi; Levi, Giovanni et al. (2003) Dlx5 regulates chondrocyte differentiation at multiple stages. Int J Dev Biol 47:335-44
Yan, Yu-Ting; Liu, Jan-Jan; Luo, Yi et al. (2002) Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol Cell Biol 22:4439-49
Hu, G; Lee, H; Price, S M et al. (2001) Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development 128:2373-84
Bendall, A J; Abate-Shen, C (2000) Roles for Msx and Dlx homeoproteins in vertebrate development. Gene 247:17-31
Hu, G; Vastardis, H; Bendall, A J et al. (1998) Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. Mol Cell Biol 18:6044-51

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