title: The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons.
abstract: 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.
authors: Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
authors: Bora
authors: 0000-0001-7439-643X
authors: B
authors: Lee
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea leeseung@snu.ac.kr leejae@ohsu.edu.
authors: Seunghee
authors: S
authors: Lee
authors: Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.|Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.|Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
authors: Soo-Kyung
authors: SK
authors: Lee
authors: Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA leeseung@snu.ac.kr leejae@ohsu.edu.|Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
authors: Jae W
authors: JW
authors: Lee
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000196:embryology* / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D054369:Agouti-Related Protein; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D013007:Growth Hormone-Releasing Hormone
keywords: Arcuate neurons; Bsx; GR; Hypothalamus; Isl1