Homeobox protein SIX4

UniProt Q61321 Organism Mus musculus Gene Arec3, Six4

Also known as: Arec3, Six4

Function

Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present in the Trex site and from a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer. Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein. Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1. Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6. Controls somitic differentiation in myocyte through MYOG transactivation. Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes. During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression. During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation. During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation. Promotes survival of sensory neurons during early trigeminal gangliogenesis. In the developing dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression. Forms gustatory papillae during development of the tongue. Also plays a role during embryonic cranial skeleton morphogenesis.

Classification

Family (Pfam): PF00046 Homeodomain, PF16878 SIX1_SD
InterPro: HD, Homeobox_CS, Homeodomain-like_sf, SIX1_SD
Functional cluster: Homeobox & Zinc-Finger Transcription Factors

Gene Ontology · 45

Neighborhood · nearest proteins

Nearest neighbours of Homeobox protein SIX4: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Homeobox protein SIX4 0.98
Homeobox protein SIX5 0.81
Hepatocyte nuclear factor 1-alpha 0.80
DNA-binding protein RFX7 0.80
Basic helix-loop-helix domain-containing protein USF3 0.80
Hepatocyte nuclear factor 1-alpha 0.80
DNA-binding protein RFX7 0.79
Hepatocyte nuclear factor 1-alpha 0.79
Metal regulatory transcription factor 1 0.79
DNA-binding protein RFX7 0.79
Sal-like protein 4 0.79
ETS-related transcription factor Elf-4 0.78

Co-cited proteins · studied together in the literature

Homeobox protein SIX4 1 shared papers
Homeobox protein SIX1 2 shared papers
Homeobox protein SIX2 1 shared papers
Homeobox protein SIX2 2 shared papers
Homeobox protein SIX5 2 shared papers
Protein phosphatase EYA3 2 shared papers
Protein phosphatase EYA2 1 shared papers
Dachshund homolog 1 1 shared papers
Protein phosphatase EYA1 1 shared papers

Literature · 20 cited papers

Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Dev. Cell · 2013
Development of gustatory papillae in the absence of Six1 and Six4. J. Anat. · 2011
Genesis of muscle fiber-type diversity during mouse embryogenesis relies on Six1 and Six4 gene expression. Dev. Biol. · 2011
Six family genes control the proliferation and differentiation of muscle satellite cells. Exp. Cell Res. · 2010
Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base. Dev. Biol. · 2010
Six1 and Six4 gene expression is necessary to activate the fast-type muscle gene program in the mouse primary myotome. Dev. Biol. · 2010
Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4. Dev. Biol. · 2009
Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs. Proc. Natl. Acad. Sci. U.S.A. · 2007
Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech. Dev. · 2007
Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis. Brain Res. · 2006
Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev. Biol. · 2006
Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS J. · 2005
… and 8 more in the literature graph

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