Biology subjects

Ramachandran, J.

Publications and source records attributed to Ramachandran, J..

3 recordsLinked to original sources

bioRxiv2023

BAF chromatin complexes do not mediate GLI transcriptional repression of Hedgehog target genes

Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated in Smarcc1 conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.

developmental biology↗

bioRxiv2022

Hedgehog regulation of epithelial cell state and morphogenesis in the larynx

The larynx enables speech while regulating swallowing and respiration. Larynx function hinges on the laryngeal epithelium which originates as part of the anterior foregut and undergoes extensive remodeling to separate from the esophagus and form vocal folds that interface with the adjacent trachea. Here we find that Sonic hedgehog (SHH) is essential for epithelial integrity in the larynx as well as the anterior foregut. During larynx-esophageal separation, low Shh expression marks specific domains of actively remodeling epithelium that undergo an epithelial to mesenchymal transition (EMT) characterized by the induction of N-Cadherin and movement of cells out of the epithelial layer. Consistent with a role for SHH signaling in regulating this process, Shh mutants undergo an abnormal EMT throughout the anterior foregut and larynx, marked by a cadherin switch, movement out of the epithelial layer and cell death. Unexpectedly, Shh mutant epithelial cells are replaced by a new population of Pax-1 expressing cells that form a rudimentary epithelium. These findings have important implications for interpreting the etiology of HH- dependent birth defects within the foregut. We propose that SHH signaling has a default role in maintaining epithelial identity throughout the anterior foregut and that regionalized reductions in SHH trigger epithelial remodeling.

developmental biology↗

bioRxiv2019

Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect effecting children and is classified by age of onset, location, and degree of spine curvature. Although rare, the onset of IS during infancy is the more severe and rapidly progressive form of the disease, leading to increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remain elusive. Here, we show that PRMT5 is critical for the regulation of terminal hypertrophic chondrocyte differentiation in the spine and models infantile IS in mouse. Conditional ablation of PRMT5 in osteochondral progenitors led to impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of several markers of endochondral ossification revealed increased COLX and Ihh expression and a dramatic reduction of Mmp13 and RUNX2 expression in the intervertebral disc and vertebral growth plate. Furthermore, we demonstrate that PRMT5 function in committed chondrogenic lineages is required for regulation of COLX expression in the adult spine. Together, our results establish PRMT5 as a critical regulator of hypertrophic chondrocyte differentiation and endochondral bone formation in spine development and maintenance.

developmental biology↗