Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.
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.
Givens
Marjory L
ML
Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
Rave-Harel
Naama
N
Goonewardena
Vinodha D
VD
Kurotani
Reiko
R
Berdy
Sara E
SE
Swan
Christo H
CH
Rubenstein
John L R
JL
Robert
Benoit
B
Mellon
Pamela L
PL
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
C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone
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