Expression of Genes in the 16p11.2 Locus during Development of the Human Fetal Cerebral Cortex

Abstract

The 593 kbp 16p11.2 copy number variation (CNV) affects the gene dosage of 29 protein coding genes, with heterozygous 16p11.2 microduplication or microdeletion implicated in about 1% of autism spectrum disorder (ASD) cases. The 16p11.2 CNV is frequently associated with macrocephaly or microcephaly indicating early defects of neurogenesis may contribute to subsequent ASD symptoms, but it is unknown which 16p11.2 transcripts are expressed in progenitors and whose levels are likely, therefore, to influence neurogenesis. Analysis of human fetal gene expression data revealed that KIF22, ALDOA, HIRIP3, PAGR1, and MAZ transcripts are expressed in neural progenitors with ALDOA and KIF22 significantly enriched compared to post-mitotic cells. To investigate the possible roles of ALDOA and KIF22 proteins in human cerebral cortex development we used immunohistochemical staining to describe their expression in late first and early second trimester human cerebral cortex. KIF22 protein is restricted to proliferating cells with its levels increasing during the cell cycle and peaking at mitosis. ALDOA protein is expressed in all cell types and does not vary with cell-cycle phase. Our expression analysis suggests the hypothesis that altered neurogenesis in the cerebral cortex contributes to ASD in 16p11.2 CNV patients.

PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice

“…Loss of PA1 in embryos leads to severe developmental defects that occur in E8.0 and no homozygous mutant has survived to E10.5, most likely due to decreased expression of BMP2 [ 21 ]. Recently, PA1 was found to be expressed in the human fetal cerebral cortex, and a homozygous missense mutation (c.274A > G; p.Ser92Gly, NM_024516.4) was found to be associated with severe neurodevelopmental disorders [ 22 , 23 ]. In addition, PA1 has been found to cooperate with phosphorylated CREB (pCREB) and glucocorticoid receptor (GR) to regulate the expression of key adipose differentiation transcription factors C/EBPβ and C/EBPδ, and the deletion of Pa1 in white and brown preadipocytes has been shown to severely disrupt adipogenesis [ 24 ].…”

Targeted Exome Sequencing of Genes Involved in Rare CNVs in Early-Onset Severe Obesity

“…Furthermore, analysis of human fetal gene expression data found that KIF22 and ALDOA are significantly enriched in progenitors compared to post-mitotic cells making them candidates for having specific roles in neurogenesis in the developing human fetal cerebral cortex. It has been suggested that neurogenesis is disrupted in 16p11.2 CNVs ( Morson et al, 2021 ). The participants in our study with rare variants in ALDOA, KIF22, TAOK2 and SEZ6L2 did not present with ASD or neurodevelopmental disorders ( Table 1 ).…”

16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids

“…Accelerated ventral telencephalic differentiation might also occur in humans with 16p11.2 deletion, as we observed in ventral organoids. Indeed, many 16p11.2 genes, such as KIF22, ALDOA, HIRIP3, PAGR1, and MAZ were found to be expressed in progenitors and could, therefore, influence neurogenesis (Roth et al, 2020, Morson et al, 2021). To date, only one study utilised organoids to examine the effect of 16p11.2 deletion on cortical NPC proliferation at one month, revealing a decreased proliferation rate and higher NEUN+ cells (Urresti et al, 2021), which is in line with our findings in ventral organoids.…”