The CHARGE syndrome ortholog CHD-7 regulates TGF-b pathways in Caenorhabditis elegans

DIEGO MARTÍN JOFRÉ; CERVINO, AILEN S.; LUCIANA F GODOY; CIRIO, MARIA CECILIA; YANOWITZ, JUDITH L.; HOCHBAUM, DANIEL

Congreso; Reunion anual de sociedades de biociencias; 2023

Dauers arelong-lived larvae specialized in survival and dispersal that are induced when Caenorhabditiselegans encounters harsh environmental conditions in early development. Ina RNAi screen looking for dauer suppressors, we identified the chromodomainhelicase CHD-7. Loss of chd-7 completely bypass dauer development orfail to complete morphogenesis, resulting in partial dauers. Mechanistically,our epistasis analysis placed CHD-7 as a TGF-β pleiotropic regulator, a pathwayrequired for dauer development. CHD7 is the only gene associated with CHARGEsyndrome, a neurodevelopmental disorder with a range of defects ranging fromhearing loss and facial dysmorphism to heart defects. RNA-seq of chd-7-depletedworms, shows misexpression of collagen genes. To explore a potential conservedfunction in vertebrates, we used Xenopus laevis embryos, an establishedmodel to study craniofacial development. Morpholino-mediated knockdown of Chd7led to a reduction in col2a1 messenger RNA (mRNA) levels, a collagen whoseexpression depends on TGF-β signaling. Both embryonic lethality andcraniofacial defects in Chd7-depleted tadpoles were partially rescued byoverexpression of col2a1 mRNA. We suggest that Chd7 has conserved roles inregulation of the TGF-β signaling pathway and pathogenic Chd7 could lead to adefective extracellular matrix deposition. @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-469750017 -1073732485 9 0 511 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0in;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}div.WordSection1{page:WordSection1;}