(The) roles of intercellular Vax1 transfer in mouse visual system development

Abstract

$Ventral anterior homeobox1$ ($VAX1$) is a homeodomain transcription factor, which is known for its role in the development of vertebrate ventral forebrain. $VAX1$ mutations in human and mice cause various malformation of ventral midline brain structures including anterior commissure, corpus callosum and optic chiasm. Previously, it was reported that Vax1 not only regulates transcription of genes in the brain areas but also promotes retinal axon growth as a translational regulator via the intercellular transfer. However, it still remains unknown about the physiological importance of the intercellular Vax1 transfer in the development. To investigate this, we generated Vax1AA mutant mice, in which conserved lysine and arginine (KR) residues that bind to heparin sulfate proteoglycan (HSPG) of retinal axons are replaced with two alanines (AA). We then examined the brain and eye development of mice at six different Vax1 gene contents. The $Vax1^{-/-}$ and $Vax1^{-/AA}$ mice failed to form the midline structures of forebrain and died perinatally due to the palate cleft. The $Vax1^{AA/AA}$ mice are also lacked of the commissures but survive by having normal palate. The optic chiasm was not formed in $Vax1^{AA/AA}$ mice, and thus the optic nerve extended to the ipsilateral brain areas. Visual information was processed properly in the retina of $Vax1^{AA/AA}$ mice, however it could not trigger vision-triggered behavior properly. Together, we propose that the intercellular transfer of Vax1 is necessary for the formation of optic chiasm and the achasmatic $Vax1^{AA/AA}$ mice can be used to understand the spatial resolution of mouse vision