The Hedgehog (Hh) signaling pathway is a major regulator of organ development that utilizes the primary cilium to regulate its transcriptional output through the GLI transcription factors. The effects of Hh signaling are primarily mediated through de-repression of GLI target genes, which in the absence of Hh inhibit transcription through an unknown mechanism. This proposal seeks to understand how GLI repressors regulate Hedgehog signaling in normal development and how this is altered in ciliopathies. We hypothesize that GLI repressors inhibit gene expression by regulating chromatin modifications at enhancers. We will determine if GLI repression occurs through the recruitment of a Histone deacetylase complex. We will also establish when GLI enhancers first acquire accessible chromatin and if their interactions with promoters require Hh signaling. We further hypothesize that GLI proteins repress enhancer activity prior to Hh activation. By testing this, we will provide the first detailed information about the early Hh morphogen response and determine if GLI transcriptional dynamics are altered in a mouse model of human ciliopathies. Collectively, these aims will provide key insights into the processes and temporal dynamics by which GLI proteins interact with and regulate chromatin to repress transcription. In addition, they will determine how GLI transcriptional networks are first established and altered in ciliopathies, providing insight into how GLI dysregulation causes structural birth defects in these syndromes.
Defects in the Hedgehog signaling pathway underlie a vast spectrum of human birth defects, including ciliopathies, holoprosencephaly, cleft palate, and a variety of limb defects such as polydactyly. This proposal seeks to fill a fundamental gap in our understanding of Hh signaling regulates gene expression through the GLI proteins. It will determine how GLI proteins interface with chromatin to regulate gene expression and how transcriptional networks are altered in ciliopathies, providing insight on how GLI dysregulation causes structural birth defects in these syndromes.
| Tabler, Jacqueline M; Rigney, Maggie M; Berman, Gordon J et al. (2017) Cilia-mediated Hedgehog signaling controls form and function in the mammalian larynx. Elife 6: |
| Huang, Bau-Lin; Trofka, Anna; Furusawa, Aki et al. (2016) An interdigit signalling centre instructs coordinate phalanx-joint formation governed by 5'Hoxd-Gli3 antagonism. Nat Commun 7:12903 |
| Norrie, Jacqueline L; Li, Qiang; Co, Swanie et al. (2016) PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud. Development 143:4608-4619 |
| Li, Qiang; Lex, Rachel K; Chung, HaeWon et al. (2016) The Pluripotency Factor NANOG Binds to GLI Proteins and Represses Hedgehog-mediated Transcription. J Biol Chem 291:7171-82 |
| Lewandowski, Jordan P; Du, Fang; Zhang, Shilu et al. (2015) Spatiotemporal regulation of GLI target genes in the mammalian limb bud. Dev Biol 406:92-103 |
| Lewandowski, Jordan P; Pursell, Taylor A; Rabinowitz, Adam H et al. (2014) Manipulating gene expression and signaling activity in cultured mouse limb bud cells. Dev Dyn 243:928-36 |
| Norrie, Jacqueline L; Lewandowski, Jordan P; Bouldin, Cortney M et al. (2014) Dynamics of BMP signaling in limb bud mesenchyme and polydactyly. Dev Biol 393:270-281 |
| Li, Qiang; Lewandowski, Jordan P; Powell, Marian B et al. (2014) A Gli silencer is required for robust repression of gremlin in the vertebrate limb bud. Development 141:1906-14 |
| Falkenstein, Kristin N; Vokes, Steven A (2014) Transcriptional regulation of graded Hedgehog signaling. Semin Cell Dev Biol 33:73-80 |
