Transcription factor activator protein-2 is required for continued luteinizing hormone-releasing hormone expression in the forebrain of developing mice

LHRH is the neuropeptide responsible for reproductive function. Prenatally, LHRH expression begins when neurons are in the olfactory pit and continues as these cells migrate into the brain. Thus, LHRH neurons maintain neurope ptide expression through very distinct environments. The regulatory interac tions that control onset and continued expression of the LHRH phenotype are unknown. To begin to address this question primary LHRH neurons were remov ed from nasal explants at different ages. A complementary DNA (cDNA) subtra ction screen was performed comparing a 3.5-days in vitro LHRH neuron [appro ximately embryonic day 15 (E15) in vivo] to two 10.5-days in vitro LHRH neu rons (approximately postnatal day 1 in vivo). The transcription factor acti vator protein-2 (AP-2 alpha) was differentially expressed and was present i n the developmentally younger LHRH neuron. In vivo analysis revealed that L HRH neurons expressed AP-2 as they migrated across the cribriform plate and into the forebrain beginning on E13.5, but that coexpression of LHRH and A P-2 was no longer detected in postnatal day 1 animals. This suggested a reg ulatory role for AP-2 in LHRH neurons. Analysis of animals lacking AP-2 alp ha revealed a dramatic decrease in forebrain LHRH neurons between E13.5 and E14.5, correlating with normal onset of AP-2 expression in LHRH neurons as they entered the central nervous system. Nasal cells robustly expressing L HRH were still present on E14.5. The continued presence of forebrain LHRH c ells is proposed based on a second marker, galanin, and lack of increased a poptotic/necrotic cells in this region. A decrease in LHRH messenger RNA in forebrain neurons indicates regulation of LHRH occurred at the transcripti onal or posttranscriptional level in mutant animals. These results indicate a developmentally restricted involvement of the transcription factor AP-2 in LHRH expression once the LHRH neurons have migrated into the forebrain, but before establishment of an adult-like distribution.