A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons

David B. Whyte, Mark A. Lawson, Denise D. Belsham, Satish A. Eraly, Chris T. Bond, John Adelman, Pamela L. Mellon

Research output: Contribution to journalArticle

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Abstract

The molecular mechanisms specifying gene expression in individual neurons of the mammalian central nervous system have been difficult to study due to the cellular complexity of the brain and the absence of cultured model systems representing differentiated central nervous system neurons. We have developed clonal, differentiated, neuronal tumor cell lines of the hypothalamic GnRH-producing neurons by targeting tumorigenesis in transgenic mice. These cells (GT1 cells) provide a model system for molecular studies of GnRH gene regulation. Here we present the identification and characterization of a neuron-specific enhancer responsible for directing expression of the rat GnRH gene in GT1 hypothalamic neurons. This approximately 300 base pair (bp) upstream region (-1571 to -1863) confers enhancer activity to a short -173-bp GnRH promoter or to a heterologous promoter only in GT1 cells. The enhancer is bound by multiple GT1 nuclear proteins over its entire length. Deletion of more than 30 bp from either end dramatically reduces activity, and even large internal fragments carrying seven of the eight DNAse I-protected elements show decreased activity. Scanning replacement mutations demonstrate that several of the internal elements are required for activity of the enhancer. Thus, the GnRH gene is targeted to hypothalamic neurons by a complex multicomponent enhancer that relies on the interaction of multiple nuclear-protein binding enhancer elements.

Original languageEnglish (US)
Pages (from-to)467-477
Number of pages11
JournalMolecular Endocrinology
Volume9
Issue number4
StatePublished - Apr 1995

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Gonadotropin-Releasing Hormone
Neurons
Base Pairing
Genes
Nuclear Proteins
Central Nervous System
Molecular Models
Tumor Cell Line
Protein Binding
Transgenic Mice
Carcinogenesis
Gene Expression
Mutation
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Whyte, D. B., Lawson, M. A., Belsham, D. D., Eraly, S. A., Bond, C. T., Adelman, J., & Mellon, P. L. (1995). A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons. Molecular Endocrinology, 9(4), 467-477.

A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons. / Whyte, David B.; Lawson, Mark A.; Belsham, Denise D.; Eraly, Satish A.; Bond, Chris T.; Adelman, John; Mellon, Pamela L.

In: Molecular Endocrinology, Vol. 9, No. 4, 04.1995, p. 467-477.

Research output: Contribution to journalArticle

Whyte, DB, Lawson, MA, Belsham, DD, Eraly, SA, Bond, CT, Adelman, J & Mellon, PL 1995, 'A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons', Molecular Endocrinology, vol. 9, no. 4, pp. 467-477.
Whyte, David B. ; Lawson, Mark A. ; Belsham, Denise D. ; Eraly, Satish A. ; Bond, Chris T. ; Adelman, John ; Mellon, Pamela L. / A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons. In: Molecular Endocrinology. 1995 ; Vol. 9, No. 4. pp. 467-477.
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