Chromatin remodeller CHD7 is required for GABAergic neuron development by promoting PAQR3 expression

Abstract

Mutations in the chromatin remodeller‐coding gene CHD7 cause CHARGE syndrome (CS). CS features include moderate to severe neurological and behavioural problems, clinically characterized by intellectual disability, attention‐deficit/hyperactivity disorder and autism spectrum disorder. To investigate the poorly characterized neurobiological role of CHD7 , we here generate a zebrafish chd7 −/− model. chd7 −/− mutants have less GABAergic neurons and exhibit a hyperactivity behavioural phenotype. The GABAergic neuron defect is at least in part due to downregulation of the CHD7 direct target gene paqr3b , and subsequent upregulation of MAPK/ERK signalling, which is also dysregulated in CHD7 mutant human cells. Through a phenotype‐based screen in chd7 −/− zebrafish and Caenorhabditis elegans , we show that the small molecule ephedrine restores normal levels of MAPK/ERK signalling and improves both GABAergic defects and behavioural anomalies. We conclude that chd7 promotes paqr3b expression and that this is required for normal GABAergic network development. This work provides insight into the neuropathogenesis associated with CHD7 deficiency and identifies a promising compound for further preclinical studies.

Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent

“…Exon 9 mutants also show more behavioral deficits than Exon 16 mutants, having reduced Mauthner cell-independent long-latency startle responses (LLCs) following acoustic stimuli, reduced O-bend responses following dark flash visual stimuli, and locomotor defects. Exon 16 mutants did show hyperactivity while in the dark, a phenotype not seen in Exon 9 mutants but one consistent with a recently described zebrafish chd7 mutant with a different CRISPR-induced mutation in the HELIc domain (Exon 17) (Jamadagni et al, 2021). Our data also show that genetic background can contribute to variation in CHARGE-related phenotypes, as Exon 16 mutants show reduced acoustic LLC responses when maintained in the TLF strain (Fig.…”

“…Having identified a defect in responses to visual stimuli, we aimed to determine if the defect extends to longer-term behavior patterns. We thus tested chd7 mutants from both the Exon 9 and Exon 16 lines in an extended visuo-motor response (VMR) assay by dark-adapting 6 dpf larvae for 30 minutes, followed by 4 hours of darkness and then 4 hours in bright light conditions (Jamadagni et al, 2021). Exon 9 mutants showed no difference in movement during the dark phase, but in the light phase showed significant hypoactivity (Fig.…”

Advances in Chromodomain Helicase DNA-Binding (CHD) Proteins Regulating Stem Cell Differentiation and Human Diseases

“…The embryologic expression of CHD7 involves several sites, including eyes, olfactory bulb cells, inner ears, etc. ( Vissers et al, 2004 ; Jamadagni et al, 2021 ). Additionally, high expression of CHD7 is also observed in undifferentiated neuroepithelium and neural crest mesenchyme as mentioned above.…”

“…Using conditional Chd7 flox allele mating with tissue-specific Cre transgenes, a recent study found that CHD7 is necessary for eye development in multiple embryonic tissues and also essential for lens development in the surface ectoderm ( Gage et al, 2015 ; Goodman and Bonni, 2019 ). Chd7 +/– mice showed hypoplasia and aplasia of posterior and lateral semicircular canals as well as innervation defects of the vestibular sensory epithelium ( Yan et al, 2020 ; Jamadagni et al, 2021 ). In all, this evidence suggests that CHD7 might play a similar role in sensory tissues as in NSCs.…”

“…Through behavioral assays and electrophysiological study, Chd7 heterozygous mice were found lacking in odor discrimination, olfactory bulb hypoplasia, and complete anosmia ( Layman et al, 2009 ). As an essential gene in stem cell differentiation, high expression of CHD7 could be found in olfactory NSCs as well as progenitor cells ( Whittaker et al, 2017 ; Jamadagni et al, 2021 ). Depletion of Chd7 results in a significant reduction of NSC proliferation in olfactory epithelials, thus leading to a decrease in olfactory receptor neurons and delayed recovery post damage ( Feng et al, 2017 ; Whittaker et al, 2017 ).…”