Analysis of haploinsufficiency in human neural progenitor cells: insights into early molecular effects of autism-related genes.

NRXN1 haploinsufficiency converges on RNA processing during cortical development, with partial transcriptomic concordance in adult autism cortex.

NRXN1 haploinsufficiency is associated with coordinated downregulation of RNA-processing genes in cortical organoids, and the convergence on mRNA nuclear export and RNA-processing genes should be interpreted cautiously and verified by direct experimental perturbation.

16p11.2 microdeletion enhances gene expression variability between human IPSC-derived forebrain interneuron progenitor cells in culture

The 574-kilobase pair 16p11.2 microdeletion raises a person’s odds for neurodevelopmental and energy balance conditions, particularly autism and obesity, with considerable clinical heterogeneity, and how much this reflects genetic versus environmental or stochastic factors is unclear. GABAergic forebrain interneurons originate from progenitors residing in the ventricular zones of the fetal ventral telencephalon, and their perturbation is implicated in 16p11.2 phenotypes, prompting investigation of how the 16p11.2 microdeletion impacts their development. Here we studied human-induced pluripotent stem cell (IPSC) derived ventral telencephalic interneuron progenitors in two-dimensional culture, comparing IPSCs isogenic except for a heterozygous 16p11.2 microdeletion to minimize confounding effects of genetic background. Single-cell RNA sequencing generated single-cell transcriptome populations for comparative bioinformatics, revealing hundreds of differentially expressed transcripts, many associated with cell signaling, chromatin biology, and neurodevelopmental conditions. Pertinently, we find that transcript level variation is significantly greater between 16p11.2 heterozygous progenitors than their isogenic wild type counterparts both for sets of genes comprising regulons, gene-sets functionally connected by transcription factor regulation, and for randomly selected gene sets. This indicates that the 16p11.2 locus itself has a genome-wide property in stabilizing transcription between cells. Regulons with the greatest increased variability in 16p11.2 heterozygous progenitors exhibit strong enrichment for cell cycle-related genes, and many are regulated by transcription factors themselves associated with autism and/or obesity, suggesting the hypothesis that enhanced transcriptional variation contributes to 16p11.2 microdeletion phenotypes.

PHOX2B polyalanine repeat mutation alters the transcriptome of neuronal progenitor cells in congenital central hypoventilation syndrome.

RNA-sequencing on the patient derived neuroepithelial stem cells (NESCs) found that the PHOX2B-PARM has a profound impact on the transcriptional profile of the cells, highlighting the use of a suitable model of CCHS/HS and providing a clear path for future experimental validation.

Molecules and Cells

Unraveling the impact of trip12 on neurodevelopment: insights from a zebrafish model

This study provides substantial evidence for the vital role of trip12 in the early stages of development, as homozygous individuals exhibited early mortality by Day 23 post-fertilization, while a substantial mortality rate was observed by Day 35 in ‘heterozygous’ mutants.

Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.

It is shown that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell models of Huntington's disease, and a panel of clinically relevant epigenetic compounds hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.