SIX3

SIX3, short for sine oculis homeobox 3, is a transcription factor of the Six family encoded by the SIX3 gene in humans. It contains a Six domain at the N-terminus and a homeobox DNA-binding domain, which together mediate DNA binding and interactions with other transcriptional regulators.

Expression and function: SIX3 is expressed in the developing forebrain and ocular tissues. It plays a crucial role in early forebrain and eye development, helping establish anterior neural identity and patterning. It participates in the regulation of signaling pathways important for anterior brain development, including sonic hedgehog (SHH), and it can influence WNT signaling in anterior regions. SIX3 operates within transcriptional complexes, often acting as a repressor in combination with co-repressors such as the Groucho/TLE family, though it can also activate target genes in certain contexts.

Clinical significance: Mutations or haploinsufficiency of SIX3 are associated with holoprosencephaly, a spectrum of forebrain and midline facial abnormalities of varying severity. Some individuals with SIX3 alterations may present with microphthalmia or other congenital ocular defects and related craniofacial anomalies.

Evolution and model organisms: SIX3 is conserved across vertebrates. In model organisms such as mice and zebrafish, Six3 orthologs are essential for proper forebrain and eye development; loss of Six3 function leads to disrupted anterior neural patterning and ocular defects, reflecting its conserved developmental role.

Overall, SIX3 functions as a key regulator of early neural and eye development, and its proper activity is critical for proper midline patterning and organogenesis.