Pituitary homeobox 3
Gene PITX3: PITX3_HUMAN
Pituitary homeobox 3 (Gene PITX3)Homo sapiens
NCBI/Entrez	5309
HGNC	9006
UniProt/Swiss-Prot/ UniProt/TrEMBL	O75364 Q5VZL2
Ensembl	ENSG00000107859
OMIM	107250, 602669
GeneCards	GC10M103979
Synonyms: Homeobox protein PITX3, MGC12766, Pituitary homeobox 3, PTX3

Pituitary homeobox 3 (Gene PITX3)Homo sapiens

The PITX3 (gene locus: Entrez: 10q25; Ensembl/HGNC: 10q24.32) gene product, pituitary homeobox 3/PITX3, is a 302 AA (31.8 kDa) transcription factor that contains a 60 AA (62-121) DNA-binding homeobox, a 14 AA (262-275) (SSLASLRLKAKQHA) paired-like homeodomain, OAR (otp, aristaless, and rax), and a 5 AA (268-272) nuclear localization signal (NLS). The bicoid-related homeoprotein is a member of the RIEG/Pitx gene family.

Pitx3 was originally identified as a human homeobox gene (mapped to 10q25) involved with anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts, Semina EV, et al. (1998) and Addison PK, et al. (2005). Pitx3 is involved in the development of the lens and mutations of this gene have been linked to aphakia, a recessive phenotype characterized by small eyes and absence of lens in mice, Semina EV, et al. (2000) and Rieger DK, et al. (2001).

Pitx3 is involved in the development of precursors of the lens and pituitary from a common pool. By late gastrulation, pitx3 expression defines a common lens and pituitary precursor field. Pitx3 is required for pituitary pre-placode formation and cell specification, Dutta S, et al. (2005). Differentiation of Pitx3+ precursors in this field is driven towards pituitary placode cell specificity by hedgehog (Shh) signaling.

Pitx3 is widely expressed in skeletal muscle under the control of a muscle specific promoter regulated by myogenic basic helix-loop-helix factors, Coulon V, et al. (2007).

Dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc, A9) are the primary cells lost during the progression of Parkinson’s disease (PD) and the essential role of Pitx3 in the development and survival of A9 mesencephalic dopaminergic (mesDA) neurons has become an area of intense interest over the past five years. Pitx3 is the first transcription factor reported to critically and selectively control the proper development of mesDA neurons and the nigrostriatal pathway, Hwang DY, et al. (2003). In 3 to 4 week old Wistar rats, Pitx3 is expressed in most dopaminergic neurons of the SN and VTA. It is coexpressed with the neuroprotective marker calbindin (CB) at higher levels in the VTA, Korotkova TM, et al. (2005). Pitx3 is specifically required for the development and maintenance of the substantia nigra (A9) neurons (Parkinson’s affected area), but not for mesDA within the tegmental area (A10) and retroubral field, Nunes I, et al. (2003), van den Munckhof P, et al. (2003), Smidt MP, et al. (2004a, 2004b).

Pitx3 is required for maintenance of substantia nigra dopaminergic neurons, Smits SM and Smidt MP, (2006), and for the regulation of tyrosine hydroxylase (TH) expression, Maxwell SL, et al. (2005). Tyrosine hydroxylase is the rate-limiting enzyme of dopamine and (nor)adrenaline biosynthesis. Pitx3 is an activator of TH expression in a cell-dependent context, suggesting that other factors and mechanisms are involved, Lebel M, et al. (2001). The mechanism of Pitx3 enhancement of TH expression in dopaminergic neurons is yet to be determined, Messmer K, et al. (2007).

Chung S, et al. (2005) used embryonic stem cells to demonstrate that pitx3 regulates specification and/or maintenance of A9-like neurons wherein it facilitates AHD2-expressing DA neuron development. Ahd2 is involved in the synthesis of retinoic acid (RA), which has a crucial role in neuronal patterning, differentiation and survival in the brain. Pitx3 may play a role in mesDA development through regulation of retinoic acid synthesis, Jacobs FM, et al. (2007). Pitx3 and Nurr1 cooperatively promote terminal maturation of mesDA neuron phenotype in murine and human ES cell cultures, Martinat C, et al. (2006). Pitx3 supports the differentiation of neural stem cells (NSC) into dopaminergic neurons with the nigrastriatal phenotype required for treatment of PD, O’Keefee FE, et al. (2008)

Data is just beginning to emerge that links Pitx3 polymorphisms with PD. Recent data linked a Pitx3 promoter SNP, rs3758549, with sporadic PD, Fuchs J, et al. (2007). Bergman O, et al. (2008) could not replicate the rs3758549 correlation, but showed a link between rs4919621 and early onset PD.

Pitx3 and other factors involved in regulation of mesDA have been reviewed recently, Alavian KN, et al. (2008).

Sigma offers antibodies and shRNAs useful for the study of PITX3 gene products..

References:

1. Addison PK, Berry V, Ionides AC, Francis PJ, Bhattacharya SS, Moore AT. (2005) Posterior polar cataract is the predominant consequence of a recurrent mutation in the PITX3 gene. Br J Ophthalmol. 89: 138-141.
2. Alavian KN, Scholz C, Simon HH. (2008) Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord. 23: 319-328.
3. Bergman O, Håkansson A, Westberg L, Nordenström K, Carmine Belin A, Sydow O, Olson L, Holmberg B, Eriksson E, Nissbrandt H. (2008) PITX3 polymorphism is associated with early onset Parkinson's disease. Neurobiol Aging. 2008 Apr 15. [Epub ahead of print].
4. Chung S, Hedlund E, Hwang M, Kim DW, Shin BS, Hwang DY, Jung Kang U, Isacson O, Kim KS. (2005) The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol Cell Neurosci. 28: 241-252.
5. Coulon V, L'Honoré A, Ouimette JF, Dumontier E, van den Munckhof P, Drouin J. (2007) A muscle-specific promoter directs Pitx3 gene expression in skeletal muscle cells. J Biol Chem. 282: 33192-33200.
6. Dutta S, Dietrich JE, Aspöck G, Burdine RD, Schier A, Westerfield M, Varga ZM. (2005) pitx3 defines an equivalence domain for lens and anterior pituitary placode. Development. 132: 1579-1590.
7. Fuchs J, Mueller JC, Lichtner P, Schulte C, Munz M, Berg D, Wüllner U, Illig T, Sharma M, Gasser T. (2007) The transcription factor PITX3 is associated with sporadic Parkinson's disease. Neurobiol Aging. 2007 Sep 28 [Epub ahead of print].
8. Hwang DY, Ardayfio P, Kang UJ, Semina EV, Kim KS. (2003) Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res. 114: 123-131.
9. Jacobs FM, Smits SM, Noorlander CW, von Oerthel L, van der Linden AJ, Burbach JP, Smidt MP. (2007) Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development. 134: 2673-2684.
10. Korotkova TM, Ponomarenko AA, Haas HL, Sergeeva OA. (2005) Differential expression of the homeobox gene Pitx3 in midbrain dopaminergic neurons. Eur J Neurosci. 22: 1287-1293.
11. Lebel M, Gauthier Y, Moreau A, Drouin J. (2001) Pitx3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site. J Neurochem. 77: 558-567.
12. Martinat C, Bacci JJ, Leete T, Kim J, Vanti WB, Newman AH, Cha JH, Gether U, Wang H, Abeliovich A. (2006) Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci U S A. 103: 2874-2889.
13. Maxwell SL, Ho HY, Kuehner E, Zhao S, Li M. (2005) Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development. Dev Biol. 282: 467-479.
14. Messmer K, Remington MP, Skidmore F, Fishman PS. (2007) Induction of tyrosine hydroxylase expression by the transcription factor Pitx3. Int J Dev Neurosci. 25: 29-37.
15. Nunes I, Tovmasian LT, Silva RM, Burke RE, Goff SP. (2003) Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci U S A. 100: 4245-4250.
16. O'Keeffe FE, Scott SA, Tyers P, O'Keeffe GW, Dalley JW, Zufferey R, Caldwell MA. (2008) Induction of A9 dopaminergic neurons from neural stem cells improves motor function in an animal model of Parkinson's disease. Brain. 131: 630-641.
17. Rieger DK, Reichenberger E, McLean W, Sidow A, Olsen BR. (2001) A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice. Genomics. 72: 61-72.
18. Semina EV, Ferrell RE, Mintz-Hittner HA, Bitoun P, Alward WL, Reiter RS, Funkhauser C, Daack-Hirsch S, Murray JC. (1998) A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat Genet. 19: 167-170.
19. Semina EV, Murray JC, Reiter R, Hrstka RF, Graw J. (2000) Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet. 9: 1575-1585.
20. Smits SM, Smidt MP. (2006) The role of Pitx3 in survival of midbrain dopaminergic neurons. J Neural Transm Suppl. 70: 57-60.
21. Smits SM, Burbach JP, Smidt MP. (2006) Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol. 78: 1-16.
22. Smidt MP, Smits SM, Burbach JP (2004b) Homeobox gene Pitx3 and its role in the development of dopamine neurons of the substantia nigra. Cell Tissue Res. 318: 35-43.
23. Smidt MP, Smits SM, Bouwmeester H, Hamers FP, van der Linden AJ, Hellemons AJ, Graw J, Burbach JP. (2004a) Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development. 131: 1145-1155.
24. van den Munckhof P, Luk KC, Ste-Marie L, Montgomery J, Blanchet PJ, Sadikot AF, Drouin J. (2003) Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development. 130: 2535-2542.