Neurons in the hypothalamic arcuate nucleus relay and translate important cues from the periphery into the central nervous system. However, the gene regulatory program directing their development remains poorly understood. Here, we report that the LIM-homeodomain transcription factor Isl1 is expressed in several subpopulations of developing arcuate neurons and plays crucial roles in their fate specification. Mice with conditional deletion of the Isl1 gene in developing hypothalamus display severe deficits in both feeding and linear growth. Consistent with these results, their arcuate nucleus fails to express key fate markers of Isl1-expressing neurons that regulate feeding and growth. These include the orexigenic neuropeptides AgRP and NPY for specifying AgRP-neurons, the anorexigenic neuropeptide αMSH for POMC-neurons, and two growth-stimulatory peptides, growth hormone-releasing hormone (GHRH) for GHRH-neurons and somatostatin (Sst) for Sst-neurons. Finally, we show that Isl1 directly enhances the expression of AgRP by cooperating with the key orexigenic transcription factors glucocorticoid receptor and brain-specific homeobox factor. Our results identify Isl1 as a crucial transcription factor that plays essential roles in the gene regulatory program directing development of multiple arcuate neuronal subpopulations.
The authors declare no competing or financial interests.
B.L., S.L., S.-K.L. and J.W.L. designed experiments. B.L. and S.L. performed experiments. B.L., S.L., S.-K.L. and J.W.L. analyzed data. B.L., S.L. and J.W.L. wrote the manuscript.
This research was supported by the National Research Foundation of Korea Basic Science Research Program [NRF-2015R1A2A1A15055611] and Bio & Medical Technology Development Program [NRF-2012M3A9C6050508]; the Korean Ministry of Science, ICT and Future Planning [MSIP-2011-0030001 to S.L.]; the National Institute of Neurological Disorders and Stroke [R01 NS054941 to S.-K.L.]; and the National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK064678 to J.W.L. and R01 DK103664 to J.W.L. and S.-K.L.]. Deposited in PMC for release after 12 months.
- Received December 8, 2015.
- Accepted August 22, 2016.