Grhl2 is required in nonneural tissues for neural progenitor survival and forebrain development

Abstract

Grainyhead-like genes are part of a highly conserved gene family that play a number of roles in ectoderm development and maintenance in mammals. Here we identify a novel allele of Grhl2, cleft-face 3 (clft3), in a mouse line recovered from an ENU mutagenesis screen for organogenesis defects. Homozygous clft3 mutants have a number of phenotypes in common with other alleles of Grhl2. We note a significant effect of genetic background on the clft3 phenotype. One of these is a reduction in size of the telencephalon where we find abnormal patterns of neural progenitor mitosis and apoptosis in mutant brains. Interestingly, Grhl2 is not expressed in the developing forebrain, suggesting this is a survival factor for neural progenitors exerting a paracrine effect on the neural tissue from the overlying ectoderm where Grhl2 is highly expressed.

Grainyhead‐like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety‐like behaviors in aged mice

“…However, despite careful examination of numerous brain sections at multiple embryonic timepoints, we could not detect any Grhl2 expression within the developing mouse brain. These results indicate both of evolutionary divergence from the zebrafish, and suggest that the previously reported apoptosis of neural progenitors in murine models is due to a secondary effect, perhaps through defects in the overlying surface ectoderm (Menke et al, ), where Grhl2 is robustly expressed (Auden et al, ).…”

“…Grhl1 had not been previously implicated in mediating neural function, and in concordance with this, we did not detect any expression of Grhl1 within the murine brain in the present study. Previous studies had shown that disruption of Grhl2 led to increased apoptosis of neural progenitors (Menke et al, ), although Grhl2 expression within the brain proper was not examined. Our previous work in zebrafish also showed that the fish orthologue of mouse Grhl2 , grhl2b was expressed within the vertebrate brain, and that transient grhl2b inhibition led to significantly elevated apoptosis at the midbrain‐hindbrain boundary (Dworkin et al, ).…”

“…Work from our group showed that a zebrafish orthologue of the Grhl family, grhl2b , is expressed within the brain, and specific antisense oligonucleotide (morpholino)‐mediated knockdown of grhl2b led to significant defects in the morphology of the midbrain‐hindbrain boundary, with concomitant increases in neural apoptosis (Dworkin et al, ). This phenotype was also largely recapitulated in a murine ENU‐mutagenesis model lacking Grhl2 (Menke et al, ), although this apoptosis was suggested to be a secondary consequence of Grhl2 loss within the surface (non‐neural) ectoderm. These data suggest that the Grhl family may play an important role in both the development, and potentially also post‐natal cognitive and motor functions in the brain.…”

MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease

“…Recent publications have demonstrated the essential functions of GRHL2 in development and differentiation with conflicting evidence on its role in EMT, and cancer progression 25,52,26 . A strong correlation of GRHL2 expression with various epithelial cells, undifferentiated progenitor cells, and chronic disease states such as atopic dermatitis and psoriasis were described 53,54 . Uniquely, hepatocytes are a rare subset of epithelial cells that do not normally express GRHL2 26 .…”

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

“…We identified the primary ciliary dyskinesia only (Pcdo) mutant in a mouse ENU mutagenesis forward genetic screen for recessive alleles leading to organogenesis phenotypes. ENU mutagenesis was performed as described previously (Stottmann, Moran et al 2011, Stottmann and Beier 2014, Menke, Cionni et al 2015, Lukacs, Roberts et al 2019) and phenotyping to recover mutant alleles was performed at early postnatal stages as part of an experiment to look for mutants with abnormal forebrain development. Pcdo mutants were initially identified by enlarged head and distended lateral ventricles upon gross dissection.…”