The neuroendocrine hypothalamus mediates homeostasis via modulating pituitary secretion of peptidc hormones. The hypothalamic paraventricular nucleus (PVN), supraoptic nucleus (SON) and anterior periventricular nucleus (aPV) are part of this network. These nuclei contain distinct secretory neurons including oxytocin (OT)-, vasopressin (VP)-, corticotropin-releasing hormone (CRH)-, thyrotropin-releasing hormone (TRH)-, and somatostatin (SS)-producing neurons.
A pair of the basic-helix-loop-helix-per-arnt-sim (bHLH-PAS) transcription
factors, SIM1 and ARNT2, is essential for the terminal determination of
the aforementioned neuroendocrine neurons. In the absence of either gene,
the precursors of these neurons fail to produce any of the hormones. Heterozygosity
of Sim1 in mice and humans also leads to early onset obesity, proposed
to be due to a hypo-development of the neuroendocrine hypothalamus (Michaud
et al., 1998) (figure1).
Using the mouse as a model organism, I am trying to understand the molecular
basis of obesity and secretory neuron differentiation by identifying the
downstream target genes controlled by Sim1. Toward this goal, I have used
an inducible gene expression system combined with microarray analysis
to identify downstream Sim1 targets. We have identified 268 potential
targets of Sim1 and are currently working toward identifying the functions
of these genes, particularly by generating conditional knockouts and mutant
analysis (figure
3) (figure
4) (figure5).
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