Counter-Balance Between Gli3 and miR-7 Is Required for Proper Morphogenesis and Size Control of the Mouse Brain

Abstract

Brain morphogenesis requires precise regulation of multiple genes to control specification of distinct neural progenitors (NPs) and neuronal production. Dysregulation of these genes results in severe brain malformation such as macrocephaly and microcephaly. Despite studies of the effect of individual pathogenic genes, the counter-balance between multiple factors in controlling brain size remains unclear. Here we show that cortical deletion of Gli3 results in enlarged brain and folding structures in the cortical midline at the postnatal stage, which is mainly caused by the increased percentage of intermediate progenitors (IPs) and newborn neurons. In addition, dysregulation of neuronal migration also contributes to the folding defects in the cortical midline region. Knockdown of microRNA (miRNA) miR-7 can rescue abnormal brain morphology in Gli3 knockout mice by recovering progenitor specification, neuronal production and migration through a counter-balance of the Gli3 activity. Moreover, miR-7 likely exerts its function through silencing target gene Pax6. Our results indicate that proper brain morphogenesis is an outcome of interactive regulations of multiple molecules such as Gli3 and miR-7. Because miRNAs are easy to synthesize and deliver, miR-7 could be a potential therapeutic means to macrocephaly caused by Gli3-deficiency.

Integrative Role of the <i>SALL4</i> Gene: From Thalidomide Embryopathy to Genetic Defects of the Upper Limb, Internal Organs, Cerebral Midline, and Pituitary

“…A recent study showed that TBX5 regulates the SALL4 gene and interacts with the SALL4 protein to regulate heart and upper limb development and establish thumb morphogenesis. Pathogenic SALL4 and TBX5 variants cause autosomal dominant Duane-radial ray syndrome (DRRS; also known as Okihiro syndrome) [ 31 , 32 ] and Holt-Oram syndrome (HOS) [ 33 ].…”

MIR3607regulates cerebral cortex development via activation of Wnt/βCat signaling

“…Interestingly, miR-7 has been shown to inhibit Pax6 protein expression without altering its mRNA levels (Needhamsen et al, 2014;Zhang et al, 2018). Moreover, the 3'UTR of Pax6 bears a functional miR-7 target site only in primates, suggesting that this interaction emerged during evolution linked to brain expansion (Needhamsen et al, 2014).…”

Turnover of RNA-binding Proteins and MicroRNAs by intrinsically disordered region-directed ZSWIM8 ubiquitin ligase during brain development

“…As the primary source of mature MiR7, MiR7a shows broad expression in the cortical plate and ventricular zone of embryonic brains ( 40 ). Simultaneous suppression of MiR7 precursors causes dysregulated expression of critical transcription factors including TP53 and PAX6, and consequentially results in defective neurogenesis and microcephaly-like brain defects at birth ( 40, 41 ). Meanwhile, an in vitro study reported that intrinsically programmed downregulation of MiR7 in oligodendrocyte precursor cells (OPCs) is important for proper fate transition of OPCs into mature oligodendrocytes (OLs), which generate insulating myelin sheath surrounding neuronal axons to facilitate fast electrical conduction ( 42 ).…”