title: Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.
abstract: Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
authors.forename: Marjory L
authors.initials: ML
authors.lastname: Givens
authors.forename: Naama
authors.initials: N
authors.lastname: Rave-Harel
authors.forename: Vinodha D
authors.initials: VD
authors.lastname: Goonewardena
authors.forename: Reiko
authors.initials: R
authors.lastname: Kurotani
authors.forename: Sara E
authors.initials: SE
authors.lastname: Berdy
authors.forename: Christo H
authors.initials: CH
authors.lastname: Swan
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
authors.forename: Benoit
authors.initials: B
authors.lastname: Robert
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry*; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051957:MSX1 Transcription Factor; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone
references.citation: Development. 1999 Nov;126(22):4965-76
references.pmid: 10529415
references.citation: J Comp Neurol. 1999 Nov 15;414(2):217-37
references.pmid: 10516593
references.citation: J Neurosci. 2000 Jan 15;20(2):709-21
references.pmid: 10632600
references.citation: Curr Opin Neurobiol. 2000 Feb;10(1):63-71
references.pmid: 10679430
references.citation: Gene. 2000 Apr 18;247(1-2):17-31
references.pmid: 10773441
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4493-8
references.pmid: 10781050
references.citation: Endocrinology. 2000 May;141(5):1823-38
references.pmid: 10803593
references.citation: Mech Dev. 2000 Jun;94(1-2):79-94
references.pmid: 10842061
references.citation: Mol Endocrinol. 2000 Sep;14(9):1509-22
references.pmid: 10976927
references.citation: Biochem Cell Biol. 2000;78(5):593-601
references.pmid: 11103950
references.citation: Neuroendocrinology. 2001 Mar;73(3):149-56
references.pmid: 11307033
references.citation: Endocrinology. 2001 Jun;142(6):2284-95
references.pmid: 11356674
references.citation: Development. 2001 Jun;128(12):2373-84
references.pmid: 11493556
references.citation: Brain Res Dev Brain Res. 2001 Oct 24;130(2):217-30
references.pmid: 11675124
references.citation: Endocrinology. 2002 Apr;143(4):1404-12
references.pmid: 11897697
references.citation: Brain Res Bull. 2002 Feb-Mar 1;57(3-4):413-8
references.pmid: 11923000
references.citation: Development. 2002 Oct;129(19):4371-86
references.pmid: 12223397
references.citation: Neurochem Res. 2002 Aug;27(7-8):831-40
references.pmid: 12374220
references.citation: Development. 2002 Nov;129(21):5029-40
references.pmid: 12397111
references.citation: Mol Endocrinol. 2002 Nov;16(11):2413-25
references.pmid: 12403831
references.citation: Dev Biol. 2003 May 1;257(1):140-52
references.pmid: 12710963
references.citation: Development. 2003 Sep;130(17):4025-36
references.pmid: 12874124
references.citation: Eur J Neurosci. 2003 Sep;18(6):1410-8
references.pmid: 14511321
references.citation: J Biol Chem. 2004 Jan 2;279(1):117-26
references.pmid: 14565958
references.citation: Cell Res. 2003 Dec;13(6):429-42
references.pmid: 14728799
references.citation: J Biol Chem. 2004 Jul 16;279(29):30287-97
references.pmid: 15138251
references.citation: Science. 1986 Dec 12;234(4782):1366-71
references.pmid: 3024317
references.citation: Anal Biochem. 1987 Apr;162(1):156-9
references.pmid: 2440339
references.citation: Nature. 1989 Mar 9;338(6211):161-4
references.pmid: 2645530
references.citation: Proc Natl Acad Sci U S A. 1989 Oct;86(20):8132-6
references.pmid: 2682637
references.citation: Neuron. 1990 Jul;5(1):1-10
references.pmid: 2196069
references.citation: Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3402-6
references.pmid: 2014260
references.citation: Endocr Rev. 1992 Nov;13(4):623-34
references.pmid: 1459046
references.citation: J Neurosci. 1993 Jul;13(7):3155-72
references.pmid: 7687285
references.citation: Dev Biol. 1993 Oct;159(2):643-56
references.pmid: 8405686
references.citation: Dev Biol. 1994 Nov;166(1):349-54
references.pmid: 7958458
references.citation: J Neurosci. 1994 Nov;14(11 Pt 1):6370-83
references.pmid: 7965042
references.citation: Mol Cell Biol. 1995 Feb;15(2):861-71
references.pmid: 7823952
references.citation: Development. 1995 Apr;121(4):1065-76
references.pmid: 7538067
references.citation: Mol Cell Biol. 1995 Nov;15(11):6169-77
references.pmid: 7565769
references.citation: Mech Dev. 1995 Sep;53(1):87-96
references.pmid: 8555114
references.citation: Nature. 1996 May 16;381(6579):235-8
references.pmid: 8622765
references.citation: Nature. 1996 May 16;381(6579):238-41
references.pmid: 8622766
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1764-9
references.pmid: 8700832
references.citation: J Neuroendocrinol. 1995 Dec;7(12):899-902
references.pmid: 8745266
references.citation: Biochem Biophys Res Commun. 1996 Oct 3;227(1):257-65
references.pmid: 8858134
references.citation: Mech Dev. 1996 Apr;55(2):185-99
references.pmid: 8861098
references.citation: Mol Cell Biol. 1997 May;17(5):2920-32
references.pmid: 9111364
references.citation: Dev Biol. 1997 May 15;185(2):165-84
references.pmid: 9187081
references.citation: Neuron. 1997 Jul;19(1):27-37
references.pmid: 9247261
references.citation: Mech Dev. 1997 Jul;65(1-2):123-33
references.pmid: 9256350
references.citation: Development. 1998 Jun;125(12):2315-25
references.pmid: 9584130
references.citation: Mol Cell Endocrinol. 1998 May 25;140(1-2):157-61
references.pmid: 9722184
references.citation: Biochemistry. 1998 Nov 17;37(46):16360-8
references.pmid: 9819228
references.citation: J Neurosci. 1999 Jul 15;19(14):5955-66
references.pmid: 10407034
references.citation: J Cell Biochem. 1999;Suppl 32-33:133-40
references.pmid: 10629112