Phenotypic differences in the brains and limbs of mutant mice caused by differences of Gli3 gene expression levels

Abstract

The genetic polydactyly/arhinencephaly mouse, Pdn/Pdn, exhibits severe polydactyly both in the fore‐and hindlimbs, agenesis of the olfactory bulbs, corpus callosum, anterior commissure, and hydrocephalus. A candidate gene for the Pdn mouse has been speculated to be Gli3, because Pdn has been considered to be an allele of Xt whose responsible gene has been clarified to be Gli3. Recently, it has been cleared that retro‐transposons are inserted into nitron 3, upstream of zinc finger domain, of the Gli3 gene in the Pdn mouse, resulting to the severe suppression of Gli3 gene expression in Pdn/Pdn embryos. Meanwhile, XtJ/XtJ mice exhibit more severe polydactyly than that of Pdn/Pdn. Arhinencephaly and microholoprosencephaly including agenesis of the olfactory bulbs, corpus callosum, anterior commissure, hippocampal commissure, habenular commissure, and posterior commissure, and moreover, the cerebral cortical plates and hippocampus are not formed in the XtJ/XtJ mice. The XtJ/XtJ mouse has a large deletion in Gli3 structural gene and shows null expression. From these corroborations, we speculated that the differences in the Gli3 gene expression levels resulted in the phenotypic differences between the Pdn/Pdn and XtJ/XtJ mice.

Genetic susceptibility in the neural tube defects induced by ochratoxin A in the genetic arhinencephaly mouse,Pdn/Pdn

“…Gli3 gene expression was depressed in the Pdn/Pdn mouse embryos (Naruse & Keino 1995; Naruse et al . 2000, 2001), because of the insertion of a transposon into intron 3 of Gli3 gene (Thien & Rüther 1999; Ueta et al .…”

“…These phenotypes are very similar to those in the human genetic disease, Greig cephalopolysyndactyly syndrome (GCPS) (Greig 1926; Naruse & Keino 1995). Gli3 is the responsible gene for the Pdn mouse (Thien & Rüther 1999; Naruse et al . 2000, 2001; Ueta et al .…”

Japanese family with Greig cephalopolysyndactyly syndrome, including bilateral seven toes, and esotropia, over three generations

“…It is evident that both diseases differ clinically from GCPS. While GCPS is caused by the most aminoterminal truncation, including the zinc-finger motifs in GLI3 genes, PAP-A is caused by carboxyterminal truncation, and HS by mutations that lie intermediate to these former disorders [4,7,8]. Acrocallosal syndrome is another disease to be differentiated because it has characteristics (similar to GCPS) such as polysyndactyly and macrocephaly [9].…”

“…It has an autosomal dominant inheritance pattern with complete penetrance and variable expressivity [1,4]. The prognosis for mental and physical development in affected patients is usually good [1,2].…”

Syndromes Caused by the Mutations in GLI3 Gene

“…Xt J homozygotes (Xt J /Xt J ) die within two days after birth or in utero with a wide range of abnormalities including gross polydactyly and syndactyly in the fore-and hindlimbs and gross malformations of the brain [55]. Xt J /Xt J , null expression mouse, exhibits more severe polysyndactyly and brain abnormalities including arhinencephaly than Pdn/Pdn which exhibits depressed expression of Gli3 gene [57].…”