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 SOX9
Homo sapiens
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Homo sapiens
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Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
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Transcription Factor Encyclopedia  BETA
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Overview

The LHX3 LIM-homeodomain transcription factor is critical for the development of the mammalian pituitary gland and its hormone-secreting cells as well as for parts of the nervous system, including roles in the specification of motor neurons [1][2]. LHX3 is part of a regulatory program of transcription factors that regulate the determination and differentiation of anterior pituitary cell types (Figure 1). The human and mouse LHX3 genes each have seven coding exons (Figure 2)[3] that generate two major mRNA transcripts (LHX3a, LHX3b)[4][5][6] from two upstream promoters [7]. The LHX3 mRNAs encode three protein isoforms: LHX3a, LHX3b, and M2-LHX3 [5][6]. The zinc-coordinated LIM domains allow LHX3 to interact with other transcription factors and with regulatory proteins. The DNA-binding homeodomain mediates interaction with cis-acting transcription regulatory regions in target genes. Recessive mutations in the LHX3 gene are associated with combined pituitary hormone deficiency (CPHD) and other features including a rigid cervical spine and deafness (Figures 3 and 4)[1]. Deficiencies in growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone result in short stature, metabolic disease, and reproductive problems for patients with LHX3 gene mutations [8][9][10][11][12][13][14][15][16]. Recently, a novel knock-in mouse model of human CPHD disease caused by the W224Ter mutation in LHX3 was developed [17].

References
  1. Colvin SC et al. LHX3 and LHX4 transcription factors in pituitary development and disease. Pediatr Endocrinol Rev, 6 Suppl 2:283-90. (PMID 19337183)
  2. Hunter CS and Rhodes SJ. LIM-homeodomain genes in mammalian development and human disease. Mol. Biol. Rep., 32(2):67-77. (PMID 16022279)
  3. Sloop KW et al. Analysis of the human LHX3 neuroendocrine transcription factor gene and mapping to the subtelomeric region of chromosome 9. Gene, 245(2):237-43. (PMID 10717474)
  4. Zhadanov AB et al. Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues. Dev. Dyn., 202(4):354-64. (PMID 7626792)
  5. Sloop KW et al. Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties. Mol. Endocrinol., 13(12):2212-25. (PMID 10598593)
  6. Sloop KW et al. An isoform-specific inhibitory domain regulates the LHX3 LIM homeodomain factor holoprotein and the production of a functional alternate translation form. J. Biol. Chem., 276(39):36311-9. (PMID 11470784)
  7. Yaden BC et al. Two promoters mediate transcription from the human LHX3 gene: involvement of nuclear factor I and specificity protein 1. Endocrinology, 147(1):324-37. (PMID 16179410)
  8. Kriström B et al. A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations. J. Clin. Endocrinol. Metab., 94(4):1154-61. (PMID 19126629)
  9. Bhati M et al. Implementing the LIM code: the structural basis for cell type-specific assembly of LIM-homeodomain complexes. EMBO J., 27(14):2018-29. (PMID 18583962)
  1. Rajab A et al. Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum. Mol. Genet., 17(14):2150-9. (PMID 18407919)
  2. Savage JJ et al. Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes. Gene, 400(1-2):44-51. (PMID 17616267)
  3. Pfaeffle RW et al. Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J. Clin. Endocrinol. Metab., 92(5):1909-19. (PMID 17327381)
  4. Bhangoo AP et al. Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J. Clin. Endocrinol. Metab., 91(3):747-53. (PMID 16394081)
  5. Netchine I et al. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat. Genet., 25(2):182-6. (PMID 10835633)
  6. Bonfig W et al. A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature. Eur. J. Pediatr., 170(8):1017-21. (PMID 21249393)
  7. Bechtold-Dalla Pozza S et al. A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency. Horm Res Paediatr, 77(1):41-51. (PMID 22286346)
  8. Colvin SC et al. Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proc. Natl. Acad. Sci. U.S.A., 108(1):173-8. (PMID 21149718)
Figures
FIGURE 1 Regulation of anterior pituitary development by transcription factors
Multiple transcription factors contribute to the establishment of the first structure of the developing pituitary, Rathke's pouch, and the subsequent differentiation of the specialized hormone-secreting cells of the mature anterior pituitary. rRP = rudimentary Rathke's pouch, ACTH = adrenocorticotropic hormone, FSH = follicle-stimulating hormone, LH = luteinizing hormone, TSH = thyroid-stimulating hormone, GH = growth hormone, PRL = prolactin, AP = anterior pituitary, IP = intermediate pituitary, PP = posterior pituitary.
This figure is from Colvin et al., 2009 and Mullen et al., 2007 (adapted).