SIX2

SIX2 (sine oculis homeobox 2) is a gene encoding a transcription factor in the sine oculis homeobox family. It is conserved in vertebrates and plays a critical role in embryonic development, especially kidney formation. The SIX2 protein contains a homeodomain for DNA binding and a SIX domain that mediates protein interactions, and it functions as part of the SIX-EYA-DACH transcriptional network.

Expression and function: In the developing kidney, SIX2 is expressed in the cap mesenchyme, a population of nephron progenitor cells. It maintains these progenitors by promoting self-renewal and delaying differentiation into pretubular aggregates that form nephrons. SIX2 antagonizes signals that drive differentiation and cooperates with co-factors such as EYA1 in gene regulatory circuits essential for nephron formation.

Developmental role: Experimental studies in mice show that loss of Six2 results in premature differentiation of nephron progenitors, rapid depletion of the progenitor pool, reduced nephron endowment, kidney hypoplasia, and perinatal lethality. Conversely, sustained SIX2 activity supports progenitor maintenance and proper zonation of nephrons.

Human relevance: In humans, SIX2 is considered essential for normal kidney development. While animal models provide strong evidence for its role, direct causal links between SIX2 mutations or dysregulation and specific human kidney disorders are being explored, and the gene is an active area of nephrogenesis research.

See also: Sine oculis family, EYA-DACH network, nephron progenitor, metanephric development.