Six3 regulates optic nerve development via multiple mechanisms

Abstract

Malformations of the optic nerve lead to reduced vision or even blindness. During optic nerve development, retinal ganglion cell (RGC) axons navigate across the retina, exit the eye to the optic stalk (OS), and cross the diencephalon midline at the optic chiasm en route to their brain targets. Many signalling molecules have been implicated in guiding various steps of optic nerve pathfinding, however much less is known about transcription factors regulating this process. Here we show that in zebrafish, reduced function of transcription factor Six3 results in optic nerve hypoplasia and a wide repertoire of RGC axon pathfinding errors. These abnormalities are caused by multiple mechanisms, including abnormal eye and OS patterning and morphogenesis, abnormal expression of signalling molecules both in RGCs and in their environment and anatomical deficiency in the diencephalic preoptic area, where the optic chiasm normally forms. Our findings reveal new roles for Six3 in eye development and are consistent with known phenotypes of reduced SIX3 function in humans. Hence, the new zebrafish model for Six3 loss of function furthers our understanding of the mechanisms governing optic nerve development and Six3-mediated eye and forebrain malformations.

Six3 in a small population of progenitors at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice

“…S1D, n=1/3). The axon pathfinding errors are consistent with the retinal phenotypes previously described in compound six3a;six3b mutant zebrafish (Samuel et al, 2016). The reduction in retinal size could be due to smaller optic cups at E10.5 (see Fig.…”

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

“…2 and Supplementary Table 6). The second most significantly associated variant is rs1004787 (P = 6.7 x 10 -17 ), near SIX3 gene, which encodes a member of the sine oculis homeobox transcription factor family involved in eye development 22 . The third SNP is rs13107325 (P = 1.3 x 10 -15 ), a missense SNP in SLC39A8 (https://www.ncbi.nlm.nih.gov/gene/64116), a gene that encodes a member of the SLC39 family of metal ion transporters, which has been associated with schizophrenia 23 as well as inflammatory bowel disease, cardiovascular and metabolic phenotypes 24 25-27 in previous GWAS ( Fig.…”

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

“…2 and Supplementary Table 5 ). The second most significantly associated variant is rs1004787 ( P < 6.7 × 10 -17 ), near SIX3 gene, which encodes a member of the sine oculis homeobox transcription factor family involved in eye development 22 . The third SNP is rs13107325 ( P < 1.3 × 10 -15 ), a missense SNP in SLC39A8 , a gene that encodes a member of the SLC39 family of metal ion transporters, which has been associated with schizophrenia 23 as well as inflammatory bowel disease, cardiovascular and metabolic phenotypes 24 25-27 in previous GWAS ( Fig.…”