In the murine hypothalamus, five of the neuroendo crine phenotypes are generated during par tially overlapping periods of time, mainly from the prolif erative neuroepithelium of the third ventricle. Cells that produce CRH are generated between embryonic days 12 and E14, with the peak generation at E13. DA and SS neurons are generated between E11 and E17, while the GHRH and TRH neurons are generated between E11 and E15, with the peak generation at E11 and E13, respectively. An interesting observation is that subpopulations of neuroendocrine cells coexisting in the same hypothalamic nucleus produce different neuropeptides. The distinct neurotransmitter phenotypes do not differ in time of generation and may appear in response to individual differentiation programs involving specific gene networks, as demonstrated for serotoniner gic, noradrenergic or dopaminergic phenotypes.

The development of the central nervous system is achieved through a delicate balance between cell prolifera tion, Inhibitors,Modulators,Libraries subsequent cell cycle withdrawal and differentiation to distinctive neuronal phenotypes. Recent observations have highlighted that both extracellular cues and intracellular signals play pivotal roles in this process. In addition, post translational histone and or DNA enzymatic modifica tions, collectively called epigenetic gene regulation, also govern the process Inhibitors,Modulators,Libraries of neurogenesis. In vivo models provide evidence that several transcrip tion factors belonging to the basic helix loop helix, homeobox and POU domain families determine the proper establishment and maturation of various neuronal phenotypes within the hypothalamic nuclei.

In spite of these observations, the inductive signals and final targets of these transcription factors are poorly characterized. Our group has previously demonstrated that the neuro trophin brain derived neurotrophic factor increases hypothalamic Trh mRNA expression in rat Anacetrapib E17 primary cultures. The BDNF effect is only observed in a population of TRH neurons that express Inhibitors,Modulators,Libraries the catalytic iso form of the BDNF receptor, TrkB. In vivo studies have also demonstrated that the expression of the TrkB receptor precedes chronologically that of TRH in the paraventricular nucleus of the rat hypothalamus, the effect of BDNF on Trh mRNA expression can also be observed in primary cultures of PVN neurons. BDNF likely regulates the acquisition and or mainte nance of this phenotype during development.

To gain a better understanding of the genes that control differen Inhibitors,Modulators,Libraries tiation of a specific phenotype in the hypothalamic neu rons, we performed a genome wide study to characterize the transcriptome of hypothalamic TRH neurons during the terminal phase of differentiation. This represented a challenge since the hypothalamic TRH cells constitute only about 2% of the total cell population.