Modeling Cornelia de Lange syndrome in vitro and in vivo reveals a role for cohesin complex in neuronal survival and differentiation

Abstract

Cornelia de Lange Syndrome (CdLS), which is reported to affect about 1 in 10,000 to 30,000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition.Cornelia de Lange syndrome can result from mutations in at least five genes: NIPBL (nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (RAD21 Cohesin Complex Component), and HDAC8 (Histone deacetylase 8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development.Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells and in vertebrate (D.rerio) brain development by knock-down and chemical inhibition experiments. An underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs and in zebrafish embryos.

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…HDAC8 plays a key role in regulating cohesion function by deacetylating one of the core cohesion proteins, SMC3, which affects mitosis as well as transcription through loss of TAD function [ 180 , 181 ]. Loss of HDAC8 activity in SVZ progenitors from 4-month old mice has been shown to reduce progenitor proliferation and differentiation [ 182 ]. Moreover, knockdown of HDAC8 in the mice embryonic carcinoma cell line P19 cells permitted the formation of embryoid bodies [ 183 ].…”

“…Moreover, knockdown of HDAC8 in the mice embryonic carcinoma cell line P19 cells permitted the formation of embryoid bodies [ 183 ]. Furthermore, loss of HDAC8 in zebrafish has been found to increase apoptosis in CNS progenitors [ 182 ]. Recently a novel intronic variant in HDAC8 was found in a large Dutch family with seven affected males presenting with X-linked ID, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome (OMIM# 309585) [ 184 ].…”

HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

“…Injections were carried out on 1-to 2-cell stage embryos. Zebrafish hdac8 full-length mRNA was injected at the concentration of 500 pg/embryo as previously described (Bottai et al, 2019). As a control the membrane red fluorescent protein (mrfp) coding mRNA was injected at the same concentration.…”

S-adenosylmethionine tRNA modification: unexpected/unsuspected implications of former/new players

“…Epidermal growth factor receptor (EGFR) is particularly abundant in neural stem cells (NSCs) [65,66]; indeed, the growth of NSCs is driven by the addition of epidermal growth factor (EGF) in the medium [67,68]. Based on this, we can speculate that a reduction of the proliferative capacity of NSCs, which have been found in an animal model of movement constraints, in which also the level of CDK5RAP1 was drastically reduced [69], could be related to an increase of the i 6 A intracellular form, which can induce a cytotoxic effect and increase autophagy, hence reducing cell proliferation, as demonstrated in a CIG model [59].…”