Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation (PubMed:20515681). During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1 (PubMed:19660448). During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway (PubMed:18321982). May also be involved in limb tendon and ligament development (PubMed:7720577). Plays a role in cell proliferation and migration (By similarity). Interacts with TCF7L2; in a canonical Wnt signaling independent manner; prevents transcription of differentiation genes in cap mesenchyme. Interacts with OSR1; form a strong repressor complex with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1 and EYA3. Expressed in phalangeal tendons, in smooth muscle and in head and body mesenchyme. First expressed at 8.5 dpc of embryo development in a restricted mesodermal subpopulation at the anterior hindbrain level. Expression of SIX2 in the developing limb begins at 11 dpc and is more pronounced ventrally. It progresses into the developing phalanges at 12.5 dpc. At 10.5 dpc expressed in the metanephric blastema, which signals the ureteric bud to evaginate from the Wolffian duct. At 11.5 dpc expressed at high levels in the dorsal anephric mesenchyme and is down-regulated where pretubular aggregates will form on the ventral side of the ureteric bud. At 14.5 dpc, expression persists in the peripheral mesenchyme of the renal cortex. At 9.5 dpc, expressed in the splanchnic mesoderm of the stomach anlage. By 10.5 dpc, expressed in the mesoderm of the posterior stomach. Expression is seen in the presumptive glandular stomach primordium at 11.5 dpc. At 12.5 dpc, becomes restricted to the mesenchyme of the antral region of the posterior stomach. At 14.5 dpc, expression remains in the antrum, just anterior to the pyloric sphincter. Down-regulated by CTNNB1 upon differentiarion. Activated by TLX1 in the kidney and repressed by HOXA2 in the branchial arch and facial mesenchyme. Six2 knockout heterozygous mice not exhibit any obvious abnormalities. However, Six2 knockout nullizygous mice die soon after birth. Belongs to the SIX/Sine oculis homeobox family.