Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation

Abstract

CHD7 mutations are implicated in a majority of cases of the congenital disorder, CHARGE syndrome. CHARGE, an autosomal dominant syndrome, is known to affect multiple tissues including eye, heart, ear, craniofacial nerves and skeleton and genital organs. Using a morpholino-antisense-oligonucleotide-based zebrafish model for CHARGE syndrome, we uncover a complex spectrum of abnormalities in the neural crest and the crest-derived cell types. We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice and differentiation and we suggest that sox10 deregulation is an important driver of the neural crest-derived aspects of Chd7 dependent CHARGE syndrome.

Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome

“…B,D,F,H). Previous work employing chd7 morphant zebrafish showed a much more marked decrease in distal enteric nerve bodies; however, the functional consequences of this observation were not explored . Interestingly, we saw a significant decrease in GI emptying at 24 h postgavage in control larvae treated with atropine (Fig.…”

Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes

“…As suggested by the pattern of cardiac defects and embryology, there are multiple lines of evidence showing that CHD7 plays a critical role in neural crest cell development and presents a stereotypic example of a neurocristopathy (Pauli, Bajpai, & Borchers, ). CHD7 is known to cooperate with PBAF to control formation of neural crest cells (Bajpai et al, ) and partially regulates Sox10 deregulation in the neural crest cells (Asad et al, ) leading to the CHARGE phenotype. Downstream Semaphorin and Robo pathways are critical to neural crest development and migration and may be involved in CHD7 ‐negative CHARGE syndrome (S R Lalani et al, ; Liu, Guo, et al, ; Schulz et al, ; Ufartes et al, ).…”

“…As suggested by the pattern of cardiac defects and embryology, there are multiple lines of evidence showing that CHD7 plays a critical role in neural crest cell development and presents a stereotypic example of a neurocristopathy (Pauli, Bajpai, & Borchers, 2017). CHD7 is known to cooperate with PBAF to control formation of neural crest cells (Bajpai et al, 2010) and partially regulates Sox10 deregulation in the neural crest cells (Asad et al, 2016) (Payne et al, 2015).…”

Experiences in feeding and gastrointestinal dysfunction in children with CHARGE syndrome

“…A study presented at the 12th International CHARGE Syndrome Conference (2015) showed that zebrafish with a knockdown of the Chd7 gene had smaller GI tracts, physically limiting the quantity of consumption compared to normal controls (Steele et al, ). A recent study looking at the neural crest‐derived phenotypes in a zebrafish model of CHARGE syndrome, showed similar results with a reduction in the number of enteric neurons and vagal neural crest cells supplying the GI tract (Asad et al, ).…”