Roles of LIM-homeodomain factors and Ldb coregulators in forebrain patterning Our previous published studies revealed important roles of the two closely related LIM-homeodomain factors Lhx6/Lhx8 in the development of cortical interneurons that derive from the medial ganglionic eminence (MGE) in the ventral telencephalon. In collaboration with John Rubensteins laboratory, we discovered that co-expression of Lhx6 and Lhx8 is required for induction of the Sonic Hedgehog (SHH) signaling molecule in the MGE. Targeted conditional inactivation of Shh in MGE neurons revealed that Shh, in turn, controls Nkx2.1, Lhx6, and Lhx8 and regulates the specification and survival of interneurons emanating from the MGE. We utilized a floxed allele of the obligatory Ldb1 coregulator of Lhx gene function to extend our analysis to transcriptional controls exerted by additional LIM-homeodomain factors on the development of a diverse array of structures in the nascent forebrain. Nkx2.1-Cremediated deletion of Ldb1 in the MGE affected development of several distinct neuronal populations. The phenotype of Ldb1/Nkx2.1-Cre mutants allowed us to conclude that Ldb1 plays an essential role in the formation of several nuclei in the hypothalamus, including the arcuate nucleus, the ventromedial hypothalamus (VMH), and the paraventricular nucleus. We noted a loss of NPY+ and POMC+ neurons in the arcuate nucleus and a disorganization of the VMH. Islet-1 stands out as a member the LIM-homeodomain gene family that is co-expressed with Ldb1 in the developing hypothalamus, notably in the developing arcuate and VMH nuclei. To determine the function of Islet-1 in hypothalamus development, we have generated Islet-1 conditional mutants by crossing the Islet-1 floxed mouse to the Nkx2.1-Cre line. Our analysis of the Islet-1/Nkx2.1-Cre mutant has revealed that the Islet-1 gene is essential for controlling the differentiation of the NPY+ and POMC+ neurons in the arcuate nucleus. Consistent with the central role of this nucleus in the regulation of energy balance, the Islet-1/Nkx2.1-Cre mutant showed phenotypes of obesity and impaired glucose metabolism. Human induced pluripotent stem (iPS) cells for the study of Smith-Lemli-Opitz Syndrome (SLOS) Supported by a Directors Challenge Award Program, our laboratory has been able to establish the premises for generating human induced pluripotent stem (iPS) cells from fibroblasts transduced by the transcription factors Sox2, Oct4, and Klf4. Extensive marker analysis identified our reprogrammed cells as iPS cells whose embryonic stem cell-like properties remain stable after multiple rounds of in vitro propagation. The derivation of iPS cells provide a platform for patient-specific in vitro disease modeling, drug screening and, ultimately, regenerative therapies. We have generated a host of iPS cell lines from children diagnosed with SLOS, a rare recessive childhood disorder caused by mutations in the DHCR7 gene. This gene encodes 7-dehydrocholesterol reductase, an enzyme that catalyzes the final step in cholesterol synthesis. Reduced function of the enzyme results in the accumulation of dehydrocholesterols and impairment of endogenous cholesterol synthesis. SLOS patients are being treated by Forbes D. Porter, the Clinical Director of NICHD. We currently examine whether SLOS iPS cells display growth parameters that distinguish them from iPS cell derived from healthy individuals. Such observation would be of preeminent importance for subsequent experiments aimed at studying the gene defects underlying the neurological deficiencies observed in these patients, establishing drug screening protocols, and developing novel avenues of therapy.

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