Homeobox protein SIX3 (SIX3)

Homeobox protein SIX3 (SIX3) is a transcription factor belonging to the sine oculis homeobox family, crucial for embryonic development, particularly for the formation of the forebrain and the eyes. SIX3 functions by binding specific DNA sequences, acting as both a transcriptional activator and repressor. It regulates multiple genes and pathways central to neural and ocular development, including direct activation of the Sonic Hedgehog (SHH) gene and repression of genes such as WNT1 and WNT8B. SIX3 also directly activates PAX6, a key regulator of eye formation, and plays a vital role in cell proliferation, cell fate specification, and tissue morphogenesis in neural and ocular tissues. Mutations in SIX3 can cause holoprosencephaly type 2 (HPE2), where the forebrain fails to properly divide, leading to severe brain and craniofacial abnormalities. Key interactions include transcriptional regulation of genes involved in anterior brain patterning, and interaction with coregulatory proteins such as TLE1 and Neuron-derived orphan receptor 1. SIX3 is not considered a direct therapeutic drug target, but its genetic variants are clinically significant as biomarkers for early-onset developmental diseases, and dysregulation may play a role in oncogenic processes.

Other names

SIX homeobox 3Sine oculis homeobox homolog 3HPE2sine oculis homeobox-like protein 3