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Pubertal Impairment in Nhlh2 Null Mice Is Associated with Hypothalamic and Pituitary Deficiencies

Genetics Branch, Center for Cancer Research, National Cancer Institute (T.C., P.D.-R., I.R.K.), and Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (S.W.), National Institutes of Health, Bethesda, Maryland 20889; Departments of Obstetrics, Gynecology, and Reproductive Biology (E.R.N.) and Medicine (U.B.K.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and Centre for Vision Science (J.G.), Queen’s University Belfast, School of Biomedical Sciences, Belfast BT12 6BA, United Kingdom

Address all correspondence and requests for reprints to: Susan Wray, Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke-National Institutes of Health, Building 35, Room 3A-1012 Bethesda, Maryland 20892-3714. E-mail: wrays{at}ninds.nih.gov; and Ilan R. Kirsch, Research Oncology, Amgen, 1201 Amgen Court West, AW1-J4144, Seattle, Washington 98119-3105. E-mail: lkirsch{at}amgen.com.

Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2^–/–) are unclear. Here we show that hypothalamic GnRH-1 content is reduced in adult Nhlh2^–/– mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2^–/– mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2^–/– mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2^–/– mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2^–/– pituitary gonadotropes as compared with wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitary-gonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH-1 neurons and, 2) in the developing and mature adenohypophysis.