DEVELOPMENT AND REGULATION OF THE LUTEINIZING HORMONE RELEASING HORMONE SYSTEM

Neurological Disorders And Stroke

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Abstract

LHRH neurons, critical for reproduction, are derived from the nasal placode and migrate into the brain where they become integral members of the hypothalamic-pituitary-gonadal axis. We study mechanism(s) underlying LHRH neuronal differentiation,migration and axonal targeting in normal/transgenic animals, and nasal explants. Intrinsic and trans-synaptic regulation of LHRH gene expression, peptide synthesis and secretion in embryonic LHRH neurons (outside the CNS) versus postnatal LHRH neurons (in the CNS) is studied using nasal explants and organotypic cultures, respectively. Previous work in our lab using nasal explants 1) showed that outgrowth of olfactory axons and migration of LHRH neurons occur in isolated olfactory pit tissue, 2) revealed olfactory axon 'guidance cues' localized to midline nasal cartilagenous tissue and 3) identified two 'developmental genes' in LHRH neurons; AP-2 (a developmental transcription factor) and a novel gene termed NELF. Over the past year, we have addressed the role of AP-2 in LHRH development using normal and AP-2 mutant mice. These studies demonstrate that AP-2 restricts LHRH expression from cells in the respiratory epithelium and is important for maintenance of LHRH gene expression as LHRH cells enter the CNS. Over the past year, we also characterized the expression pattern of NELF during development NELF is primarily limited to PNS and CNS tissues. Pertinent to our work, the encoded protein is expressed in the olfactory system and migrating LHRH neurons. Antisense experiments demonstrated that knock-down of NELF decreased olfactory axon outgrowth and subsequent LHRH neuronal migration. We hypothesize NELF acts via a homophilic interaction. Future studies are directed at understanding the role of NELF during development and the downstream signals activated by this molecule that result in axon outgrowth and cell movement. To understand the regulation of LHRH neurons and their cellular responses, we are examining the activity of LHRH neurons in nasal explants. We have found that there are important maturational events that are intrinsic properties of these cells. We have also demonstrated that LHRH neurons maintained in vitro can release LHRH peptide and rapidly synthesize new peptide in response to a secretory event. Work in progress is focused on: 1) isolation of the midline cues which influence olfactory axon outgrowth; 2) the role of NELF and other molecules in LHRH migration, 3) whether LHRH neurons maintained in nasal explants (devoid of brain influences) show rhythmic activity patterns and if so the mechanisms underlying this rhythm, and 4) genes differentially expressed in LHRH neurons as a function of developmental and reproductive state.