title: Anteroposterior Limb Skeletal Patterning Requires the Bifunctional Action of SWI/SNF Chromatin Remodeling Complex in Hedgehog Pathway.
abstract: Graded Sonic hedgehog (Shh) signaling governs vertebrate limb skeletal patterning along the anteroposterior (AP) axis by regulating the activity of bifunctional Gli transcriptional regulators. The genetic networks involved in this patterning are well defined, however, the epigenetic control of the process by chromatin remodelers remains unknown. Here, we report that the SWI/SNF chromatin remodeling complex is essential for Shh-driven limb AP patterning. Specific inactivation of Srg3/mBaf155, a core subunit of the remodeling complex, in developing limb buds hampered the transcriptional upregulation of Shh/Gli target genes, including the Shh receptor Ptch1 and its downstream effector Gli1 in the posterior limb bud. In addition, Srg3 deficiency induced ectopic activation of the Hedgehog (Hh) pathway in the anterior mesenchyme, resulting in loss of progressive asymmetry. These defects in the Hh pathway accompanied aberrant BMP activity and disruption of chondrogenic differentiation in zeugopod and autopod primordia. Notably, our data revealed that dual control of the Hh pathway by the SWI/SNF complex is essential for spatiotemporal transcriptional regulation of the BMP antagonist Gremlin1, which affects the onset of chondrogenesis. This study uncovers the bifunctional role of the SWI/SNF complex in the Hh pathway to determine the fate of AP skeletal progenitors.
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: Rho Hyun
authors.initials: RH
authors.lastname: Seong
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D016207:Cytokines; D047108:Embryonic Development / Q000235:genetics; D005121:Extremities / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D005809:Genes, Regulator; D053823:Hedgehog Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D018878:Limb Buds / Q000254:growth & development / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D019485:Bone Morphogenetic Proteins; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C113178:Grem1 protein, mouse; C000606240:Ptch1 protein, mouse; C445179:SWI-SNF-B chromatin-remodeling complex; C465570:Shh protein, mouse