Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

PITX2

contributors: shn/npt/pgu/shn - updated : 18-01-2017

HGNC name	paired-like homeodomain 2
HGNC id	9005

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth gingiva     moderately Homo sapiens   mouth tooth       Homo sapiens Endocrine neuroendocrine pituitary     highly Homo sapiens Nervous brain         Homo sapiens Adult   brain         Homo sapiens Fetal Visual eye       moderately Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular       moderately

cells

System Cell Pubmed Species Stage Rna symbol Digestive epithelial cell Homo sapiens Digestive odontoblast Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	Rathke pouch at an early stage of pituitary and dental development, vitelline vessels, mesenchyme of limb,
	trabecular meshwork

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	POU specific and POU homeo (helix-turn-helix) domains
	four transcriptional domains with left and right compoments
	C terminal OAR domain found in homeo domain proteins highly expressed in craniofacial tissues, and that can each independently interact with factors to regulate its transcriptional activity

mono polymer

homomer , dimer

HOMOLOGY

interspecies	ortholog to Pitx2, Rattus norvegicus
	ortholog to Pitx2, Mus musculus
	ortholog to pitx2, Danio rerio
	ortholog to PITX2, Pan troglodytes

intraspecies

homolog to PTX1

Homologene

FAMILY

RIEG/PITX homeobox family

CATEGORY

DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus
text	expressed in neural crest and the mesoderm-derived precursors of the periocular mesenchyme
	co-localizes with PAWR in nucleus

basic FUNCTION	a critical role for pitx2 in left-right asymmetry and may function at an intermediate step in cardiac morphogenesis and embryonic rotation
	a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes
	a transcriptional marker of tooth development
	acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression
	involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin
	plays an important role in development and maintenance of anterior structures
	plays with EBAF, LEFTYB, NODAL a critical role in the intermediate steps controlling left-right asymetry, cardiac morphogenesis and embryonic rotation, in response to NODAL
	RNA polymerase 2 transcription factor, involved in the regulation of heart development through the regulation of NPPA and PLOD1 gene expression and NKX2-5 transcriptional activity
	plays an important role in corneal development
	plays an essential role in neural crest in regulating an extrinsic factor(s) required for development of the optic nerve
	controls the number of muscle precursors through TBX1 in the first branchial arch mesodermal core
	acts as a transcriptional activator but can be repressed through its interaction with other transcription factors
	required in neural crest for specification of corneal endothelium, corneal stroma and the sclera and or normal development of ocular blood vessels
	plays a key role in pulmonary myocardium formation
	also plays a central role in determining left/right asymmetry
	plays an important role during cardiac asymmetric development
	homeodomain transcription factor, functioning to regulate the early stages of smooth muscle cell differentiation
	first demonstrated upstream activator of myogenesis in the extraocular muscles
	regulates SLC13A3 transcription and modulates with SLC13A3 responses to oxidative stress in ocular cells (
	LHX6 and the PITX2 homeodomain transcription factor have overlapping expression patterns during tooth and craniofacial development
	is the first transcriptional marker of tooth development and is specifically expressed in the oral and dental epithelium
	influences the expression of transcription factors and signaling molecules involved in the differentiation of the cushion mesenchyme during heart development
	PITX2 and PITX3 are key regulators of the intracellular redox state preventing DNA damage as cells undergo differentiation
	is essential for axis formation, and it acts as a direct regulator of GDF1 expression by binding to enhancers within neighbouring genes
	dose-dependent relation between PITX2 expression and the expression of Atrial fibrillation (AF) susceptibility genes, calcium handling, and microRNAs and identify a complex regulatory network orchestrated by PITX2 with large impact on atrial arrhythmogenesis susceptibility
	might play an important role in regulating gene expression and electrical function of the adult left atrium (LA)

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

sensory transduction/vision

	PITX2/Cyclin D pathway might be a prototypic module used to regulate cell-type-specific proliferation during embryogenesis
	TGFB1-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation
	CITED2 plays a role in left–right patterning through the NODAL-PITX2C pathway

a component

INTERACTION

DNA	bicoid and bicoid-like elements in the Dlx2 promoter (

RNA

small molecule

protein	POU domain class 1 transcription factor 1, Pit1 (
	glial cells missing homolog 1, GCM1 (pmid/ 15385555)
	beta-catenin, CTNNB1 and lymphoid enhancer factor, LEF-1 (
	ANF (atrial natriuretic factor), prolactin promoters are targets of PITX2
	TBX1
	forkhead box C1, FOXC1
	C-terminal leucine zipper domain of PRKC apoptosis WT1 regulator, PAWR (
	binds and activates transcription of the MYF5 and MYOD1 promoters, indicating these genes are direct targets (
	WDR5 (
	interaction with SHROOM3 (SHROOM3 and CDH2 function cooperatively downstream of PITX2 to directly regulate cell shape changes necessary for early gut tube morphogenesis)
	directly interacts with PITX2 to inhibit PITX2 transcriptional activities and activation of multiple promoters
	PITX2 associates with PAXIP1-containing histone H3 lysine 4 methyltransferase complex
	PITX2 is similarly reactivated in postnatal/adult heart at distinct heart failure (HF) phenotypes, suggesting that PITX2 is involved, directly or indirectly, in the regulation of MYF5 expression in cardiomyocytes
	PITX2-mediated repression of DEPDC1B expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling
	potent BARX1 functions in intestinal rotation and stomach myogenesis occur through ISL1, PITX1, SIX2 and PITX2, intermediary transcription factors
	SOX2 and LEF1 interact with PITX2 to regulate incisor development and stem cell renewal

cell & other

REGULATION

Other

induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes (

ASSOCIATED DISORDERS

corresponding disease(s)

RIEG1 , IHG2 , RGDC

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional         duplication of PITX2 is causal of iris hypoplasia constitutional germinal mutation     loss of function with increased susceptibility to tetralogy of Fallot (TOF) constitutional germinal mutation       induces cerebral small-vessel disease constitutional germinal mutation     loss of function association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect

Susceptibility

to atrial arrhythmias (see ATFB5) to atrial fibrillation (AF) to tetralogy of Fallot (TOF)

Variant & Polymorphism other	has multiple targets that are relevant to the predisposition to atrial arrhythmia
	enhancer regulating PITX2c expression, and activity of this enhancer is modulated by SNP rs2595104, which almost completely abolished binding of TFAP2A, leading to decreased PITX2c expression and potentially a higher risk of AF

Candidate gene
Marker	PITX2 methylation is useful as a biomarker of poor outcome of prostate cancer
Therapy target
	System Type Disorder Pubmed cardiovascular rythm   . PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF

ANIMAL & CELL MODELS

	Pitx2 gene-deleted mice display defective body-wall closure, right pulmonary isomerism, altered cardiac position, arrest in turning and a block in the determination and proliferation events of anterior pituitary gland and tooth organogenesis (
	Pitx2-/- mice embryos had correctly oriented, but arrested, embryonic rotation and right pulmonary isomerism, defective development of the mandibular and maxillary facial prominences, regression of the stomodeum and arrested tooth development (
	Complete Pitx2 loss of function in mice results in agenesis or severe disruption of periocular mesenchyme structures and extrinsic defects in early optic nerve development (
	neural crest-specific Pitx2 knockout mice are viable and exhibit an optic nerve phenotype in which the eyes are progressively displaced towards the midline until they are directly attached to the ventral hypothalamus (
	ablation of unilateral Pitx2 expression in mice impairs asymmetric remodelling of the branchial arch artery system, resulting in randomized laterality of the aortic arch
	Pitx2c-deficient mice do not develop a pulmonary myocardial sleeve because they fail to form the initial pulmonary myocardial cells