SIX4
Description
The SIX4 (SIX homeobox 4) is a protein-coding gene located on chromosome 14.
Homeobox protein SIX4 is a protein that in humans is encoded by the SIX4 gene.
SIX4, also known as Sine oculis homeobox homolog 4, acts as a transcriptional regulator, functioning both as a repressor and activator of gene expression. It binds to specific DNA sequences within its target genes, influencing processes like cell differentiation, migration, and survival. SIX4 activates gene expression by binding to the Trex site (5'-[CAT]A[CT][CT][CTG]GA[GAT]-3') and the MEF3 site (5'-TCA[AG][AG]TTNC-3') within muscle-specific gene enhancers. Collaborating with EYA proteins, SIX4 activates target genes through protein interactions and nuclear translocation of EYA proteins. It synergizes with SIX1 to regulate target genes involved in the development of various organs, including muscles, kidneys, gonads, ganglia, olfactory epithelium, and cranial skeleton. During muscle development, SIX4 plays a crucial role in several stages: it controls the formation of hypaxial myogenic progenitors in the dermomyotome by activating PAX3, facilitates the migration of these progenitors from the ventral lip to the limb buds by activating PAX3, MET, and LBX1, and regulates myoblast determination by activating MYF5, MYOD1, and MYF6. Moreover, SIX4 regulates somitic differentiation in myocytes through MYOG activation, participates in synaptogenesis and sarcomere organization during myofiber specialization by activating the fast muscle program in the primary myotome, leading to increased expression of fast muscle genes like ATP2A1, MYL1, and TNNT3. Concurrently, SIX4 activates inhibitors of slow muscle genes such as SOX6, HRASLS, and HDAC4, thereby preventing the activation of these genes. During muscle regeneration, SIX4 negatively regulates the differentiation of muscle satellite cells by downregulating MYOG expression. In kidney development, SIX4 regulates the early stages of metanephros development and ureteric bud formation by influencing the expression of GDNF, SALL1, PAX8, and PAX2. SIX4 also participates in gonad development, regulating both testis determination and size. During gonadal sex determination, SIX4 activates ZFPM2 by binding to a MEF3 consensus sequence, resulting in SRY upregulation. In gonadal size determination, SIX4 activates NR5A1 by binding to a MEF3 consensus sequence, influencing gonadal precursor cell formation. During olfactory development, SIX4 mediates the specification and patterning of the olfactory placode through fibroblast growth factor and BMP4 signaling pathways, and it regulates epithelial cell proliferation during placode formation. SIX4 promotes the survival of sensory neurons during early trigeminal gangliogenesis and upregulates SLC12A2 transcription in the developing dorsal root ganglia. It also regulates early thymus/parathyroid organogenesis by controlling the expression of GCM2 and FOXN1 and contributes to the formation of gustatory papillae during tongue development. SIX4 plays a role in embryonic cranial skeleton morphogenesis. Furthermore, SIX4 interacts with EYA3, cooperating with it to activate target genes through protein interaction and nuclear translocation of EYA3.
SIX4 is also known as AREC3.
