Molecular Convergence of Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although there can be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations.

Summary of psychometric properties of the French version of the questionnaire mental health profile of etindele (MHPE)

“…Identification of early signs of clinical parameters of mental diseases whatever the methodology, before invasive investigations, may reduces significantly onset of prevalence [16][17][18][19][20][21][22]. An environmental factor of depression, stress or anxiety, can be easily prevents with a regular self report of information by participant himself or professional healthcare.…”

Stress: Two Sides of a Coin

“…They are sometimes a sign of a long accumulation of small worries and frustrations that can severely affect the quality of life. For some people, prolonged exposure to stress can even lead to depression [22,23]. Stress can lead us to change our lifestyle.…”

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex

“…27 TCF4 has also been found to participate in the induction of cell cycle arrest in human colorectal cancer cell lines. 28 In a study by Chen and colleagues, 18 stable knockdown of TCF4 in a neural progenitor cell line derived from the human fetal ventral midbrain brought about changes in gene expression characteristic of differentiating rather than proliferating cells. Although no effect on cell proliferation was observed, the authors speculated that reduced dosage of TCF4 could result in precocious differentiation of some neural progenitors that had prematurely exited the cell cycle.…”

“…Although no effect on cell proliferation was observed, the authors speculated that reduced dosage of TCF4 could result in precocious differentiation of some neural progenitors that had prematurely exited the cell cycle. 18 The neural progenitor cell line we used for this study was derived from the cortical neuroepithelium of a 12-week human fetus. 19 This cell line has been shown to differentiate into β-III tubilin-positive neurons and GFAP-positive astrocytes following removal of 4-OHT and the growth factors bFGF and EGF.…”

“…17 Stable knockdown of TCF4 in neural progenitor cells from the human fetal midbrain has been reported to result in gene expression changes more characteristic of differentiating than proliferating cells, suggesting effects on the timing of neural differentiation. 18 However, to date, effects of TCF4 manipulation in cells from the developing human cerebral cortex have not been explored. In the present study, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from human fetal neocortex in order to explore molecular and cellular mechanisms through which TCF4 perturbation could interfere with early cortical development.…”