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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

The PAired-boX (PAX) gene family is a developmentally crucial small gene family, that encodes a set of well-characterized transcription factors.They are named for the paired box DNA-binding domain that is common and conserved in all the family members [1]. In addition, they are subclassified into four subgroups according to structural similarity, i.e. the presence or absence of an octapeptide region and the presence, absence or truncation of a homeodomain[2]. Nine members of the family have been described in mammals, with orthologues present in worms, flies, frogs, fish and birds.

PAX genes are regulators of tissue development and cellular differentiation in embryos, acting to promote cell proliferation, cell-lineage specification, migration and survival[3][2]. In addition, PAX genes have been shown to play an important role in human disease as cancer and genetic disorders[4]. The expression of PAX genes is observed primarly during fetal development, and typically it is down-regulated in the adult organism. However, in a few tissues, the expression of PAX genes persists into adult life[5]. While the absence of PAX genes has definitive deleterious consequences, little is known regarding the specific mechanisms by which PAX proteins influence organogenesis. Examples of target organs and tissues for the expression of PAX proteins during organogenesis are the skeleton (PAX1 and 9), central nervous system (PAX2, 3, 5, 6, 7, and 8) kidney (PAX2 and 8), B-cells (PAX5), thyroid (PAX8), pancreas (PAX4 and 6) and skeletal muscle (PAX3 and 7). Mouse transgenic models that have mutations disrupting the expression of these specific PAX genes exhibit abnormal development or agenesis of the corresponding target tissues [6][7][8].

PAX8 belongs to the PAX2/PAX5/PAX8 subgroup containing an octapeptide domain and a truncated homeodomain (Fig. 1). In the mouse embryo, the PAX8 gene is expressed in the developing central nervous system, kidney, and thyroid. In the adult organism PAX8 is expressed exclusively in thyroid and kidney[9][10]. PAX8 is the only member of the family expressed in the thyroid tissue and in the mouse it has been demonstrated to be involved both in the organogenesis/morphogenesis of the thyroid gland[11] and in thyroid follicular cell differentiation[12]. The molecular mechanisms involved in PAX8 control of thyroid cell differentiation have been investigated in details, both in vitro and in vivo. In mature thyroid follicular cells, PAX8 regulates the expression of thyroglobulin [13] , thyroperoxidase[14] and sodium/iodide symporter[15] genes. Interestingly, PAX8 knockout mice show a severe thyroid phenotype, being the thyroid gland barely visible and lacking the follicular cells, the most abundant cell population of the thyroid gland[11]. In addition, in these mice the expression of thyroid-specific markers, such as thyroglobulin and thyroperoxidase, cannot be detected. All together, these studies led to the conclusion that PAX8 is needed for proper survival and differentiation of thyrocytes. In humans, PAX8 mutations have been associated with some cases of congenital hypothyroidism[16][17][18][19][20][21][22][23]. In addition, chromosomal translocation involving the PAX8 gene in thyroid cancer have been identified suggesting that it may have an oncogenic capability when expressed either as part of a fusion gene, or as a whole gene[24],[3],[4].

References
  1. Xu W et al. Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations. Cell, 80(4):639-50. (PMID 7867071)
  2. Chi N and Epstein JA. Getting your Pax straight: Pax proteins in development and disease. Trends Genet., 18(1):41-7. (PMID 11750700)
  3. Wang Q et al. Pax genes in embryogenesis and oncogenesis. J. Cell. Mol. Med., 12(6A):2281-94. (PMID 18627422)
  4. Robson EJ et al. A PANorama of PAX genes in cancer and development. Nat. Rev. Cancer, 6(1):52-62. (PMID 16397527)
  5. Blake JA et al. Perplexing Pax: from puzzle to paradigm. Dev. Dyn., 237(10):2791-803. (PMID 18816860)
  6. Stoykova A and Gruss P. Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J. Neurosci., 14(3 Pt 2):1395-412. (PMID 8126546)
  7. Dressler GR et al. Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature, 362(6415):65-7. (PMID 8383297)
  8. Epstein DJ et al. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell, 67(4):767-74. (PMID 1682057)
  9. Parlato R et al. An integrated regulatory network controlling survival and migration in thyroid organogenesis. Dev. Biol., 276(2):464-75. (PMID 15581879)
  10. Plachov D et al. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development, 110(2):643-51. (PMID 1723950)
  11. Mansouri A et al. Follicular cells of the thyroid gland require Pax8 gene function. Nat. Genet., 19(1):87-90. (PMID 9590297)
  12. Pasca di Magliano M et al. Pax8 has a key role in thyroid cell differentiation. Proc. Natl. Acad. Sci. U.S.A., 97(24):13144-9. (PMID 11069301)
  1. Espinoza CR et al. Thyroid transcription factor 1 and Pax8 synergistically activate the promoter of the human thyroglobulin gene. J. Mol. Endocrinol., 27(1):59-67. (PMID 11463576)
  2. Zannini M et al. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol. Cell. Biol., 12(9):4230-41. (PMID 1508216)
  3. Ohno M et al. The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription. Mol. Cell. Biol., 19(3):2051-60. (PMID 10022892)
  4. Tonacchera M et al. Genetic analysis of the PAX8 gene in children with congenital hypothyroidism and dysgenetic or eutopic thyroid glands: identification of a novel sequence variant. Clin. Endocrinol. (Oxf), 67(1):34-40. (PMID 17437516)
  5. de Sanctis L et al. Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability. J. Clin. Endocrinol. Metab., 89(11):5669-74. (PMID 15531527)
  6. Meeus L et al. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocrinol. Metab., 89(9):4285-91. (PMID 15356023)
  7. Bereket A et al. Analysis of the PAX8 gene in congenital hypothyroidism caused by different forms of thyroid dysgenesis in a father and daughter. J. Pediatr. Endocrinol. Metab., 17(7):1021-9. (PMID 15301052)
  8. Vilain C et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J. Clin. Endocrinol. Metab., 86(1):234-8. (PMID 11232006)
  9. Macchia PE et al. Molecular genetics of congenital hypothyroidism. Curr. Opin. Genet. Dev., 9(3):289-94. (PMID 10377281)
  10. Macchia PE et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat. Genet., 19(1):83-6. (PMID 9590296)
  11. Damante G. Thyroid defects due to Pax8 gene mutations. Eur. J. Endocrinol., 139(6):563-6. (PMID 9916856)
  12. Placzkowski KA et al. The Role of the PAX8/PPARgamma Fusion Oncogene in Thyroid Cancer. , 2008:672829. (PMID 18989374)
Figures
FIGURE 1 PAX family members subgroups
The nine PAX genes are divided into four subgroups based on the presence or absence of structural regions such as a DNA-binding homeodomain, a partial homeodomain and an octapeptide motif. PAX genes encode also a carboxy-terminal transactivation domain. All PAX genes contain the paired domain and all except PAX4 and PAX6 (group IV) contain an octapeptide region. PAX2, PAX5 and PAX8 (group II) have a truncated homeodomain, while PAX1 and PAX9 (group I) do not have the homeodomain region. PAX3 and PAX7 (Group III) have all the three domains.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.