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Islet 1 Specifies the Identity of Hypothalamic Melanocortin Neurons

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Islet 1 Specifies the Identity of Hypothalamic Melanocortin Neurons Islet 1 specifies the identity of hypothalamic PNAS PLUS melanocortin neurons and is critical for normal food intake and adiposity in adulthood Sofia Nasifa,1, Flavio S. J. de Souzaa,b,1, Laura E. Gonzáleza, Miho Yamashitac, Daniela P. Orqueraa, Malcolm J. Lowc, and Marcelo Rubinsteina,b,c,2 aInstituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina; bFacultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina; and cDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105 Edited by Sylvia M. Evans, University of California San Diego, La Jolla, CA, and accepted by the Editorial Board March 9, 2015 (received for review January 12, 2015) Food intake and body weight regulation depend on proper expres- other genes necessary for POMC processing and melanocortin re- sion of the proopiomelanocortin gene (Pomc) in a group of neurons lease are common to most other neurons expressing neuropeptide located in the mediobasal hypothalamus of all vertebrates. These brain genes. Cotransmitters such as glutamate, GABA, or cocaine- neurons release POMC-encoded melanocortins, which are potent an- and amphetamine-regulated transcript (CART) are found only orexigenic neuropeptides, and their absence from mice or humans in fractions of hypothalamic POMC neurons (6, 7), as are leptin, leads to hyperphagia and severe obesity. Although the pathophysi- insulin, estrogen, and serotonin receptors (8–10). ology of hypothalamic POMC neurons is well understood, the genetic It has been shown, first in the invertebrate worm Caenorhabditis program that establishes the neuronal melanocortinergic phenotype elegans, that the identity of a neuronal type is specified early in and maintains a fully functional neuronal POMC phenotype through- development by the expression of a specific transcription factor out adulthood remains unknown. Here, we report that the early (TF) that promotes terminal differentiation of postmitotic neu- expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) rons into their final functional phenotype (11). A TF acting on in the developing hypothalamus promotes the terminal differentiation terminal specification binds to cis-acting regulatory motifs present of melanocortinergic neurons and is essential for hypothalamic Pomc in target genes that determine the neurotransmitter phenotype expression since its initial onset and throughout the entire lifetime. We and may continue later in life maintaining the same postmitotic detected ISL1 in the prospective hypothalamus just before the onset of identity (11). A similar scenario has been found more recently in Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 vertebrates, after the identification of the genetic programs that bindsinvitroandinvivotocriticalhomeodomainbindingDNAmotifs give birth and maintain serotonergic (12), dopaminergic (13), and present in the neuronal Pomc enhancers nPE1 and nPE2, and muta- noradrenergic neurons (14) in the mouse nervous system. Less tions of these sites completely disrupt the ability of these enhancers to is known, however, about the specification of neuronal types drive reporter gene expression to hypothalamic POMC neurons in expressing neuropeptide genes. transgenic mice and zebrafish. ISL1 is necessary for hypothalamic Pomc Transcriptional regulation of Pomc in the hypothalamus is con- expression during mouse and zebrafish embryogenesis. Furthermore, veyed by a distal upstream regulatory cis-acting module that contains conditional Isl1 inactivation from POMC neurons impairs Pomc expres- sion, leading to hyperphagia and obesity. Our results demonstrate that Significance ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity Foodintakeandbodyweightregulationdependonagroupof throughout the entire lifespan. hypothalamic neurons that release satiety-induced neuropeptides known as melanocortins. Central melanocortins are encoded by hypothalamus | melanocortin | obesity | Isl1 | pomc the proopiomelanocortin gene (Pomc), and mice and humans carrying deleterious mutations in the Pomc gene display hyper- egulation of body weight and energy balance in vertebrate phagia and severe obesity. Although the importance of these Ranimals is controlled by hypothalamic circuits that integrate neurons is well understood, the genetic program that establishes environmental, peripheral, and central signals to promote food in- hypothalamic melanocortin neurons and maintains normal Pomc take or satiety (1). In particular, a set of neurons located in the expression levels remains unknown. Here, we combined molecu- arcuate nucleus of the hypothalamus expresses proopiomelanocortin lar neuroanatomical and biochemical analyses with functional (Pomc),agenethatencodestheanorexigenic melanocortins α-, genetic studies in transgenic mice and zebrafish and discovered β-andγ-melanocyte-stimulating hormone (MSH). POMC neurons that the transcription factor Islet 1 determines the identity of sense leptin, insulin and glucose levels, and receive multiple syn- central melanocortin neurons during early brain development and aptic contacts which, together, orchestrate neuronal activity and is critical for melanocortin-induced satiety and normal adiposity determine the pattern of melanocortins release (2, 3). The physi- throughout the entire lifetime. ological relevance of the central melanocortin system can be readily appreciated in hypothalamic Pomc-deficient mice, which are hy- Author contributions: S.N., F.S.J.d.S., L.E.G., M.J.L., and M.R. designed research; S.N., F.S.J.d.S., BIOLOGY L.E.G., M.Y., D.P.O., and M.R. performed research; M.J.L. and M.R. contributed new reagents/ DEVELOPMENTAL perphagic and display early onset severe obesity (4). In addition, analytic tools; S.N., F.S.J.d.S., L.E.G., M.J.L., and M.R. analyzed data; and S.N., F.S.J.d.S., and humans carrying biallelic null POMC variants are also severely M.R. wrote the paper. obese (5). Although much has been learned about the physiology of The authors declare no conflict of interest. central melanocortinergic neurons and the pathological con- This article is a PNAS Direct Submission. S.M.E. is a guest editor invited by the Editorial sequences of their malfunction, the genetic programs that de- Board. termine the phenotypic identity of these neurons and maintain the 1S.N. and F.S.J.d.S. contributed equally to this work. neuronal POMC phenotype throughout the entire lifespan remain 2To whom correspondence should be addressed. Email: [email protected]. to be explored. A unique feature that specifies the neuronal mel- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. anocortinergic phenotype is, in fact, the expression of Pomc because 1073/pnas.1500672112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1500672112 PNAS | Published online March 30, 2015 | E1861–E1870 Downloaded by guest on September 24, 2021 two enhancers, named “neuronal Pomc enhancers” (nPE1 and nPE2), with a strong expression in the future Rathke’s pouch and in the + which are highly conserved in mammals (15). Expression studies in first pharyngeal arch, but no ACTH neurons are evident yet. transgenic mice showed that nPE1 and nPE2 drive completely Coexpression of Isl1 and Pomc was observed at E10.5 and E12.5, + overlapping spatiotemporal enhancer activities to the ∼3,000 when every single ACTH neuron showed ISL1 nuclear labeling POMC neurons present in the mouse ventromedial hypothalamus (Fig. 1A, Insets), indicating that Pomc expression commences during embryogenesis as well as in adulthood (16) and only the a few hours later than the expression onset of Isl1 in the de- + concurrent removal of both enhancers from the mouse Pomc locus veloping hypothalamus (Fig. 1A). ISL1 cells accumulate in the by targeted mutagenesis reduced Pomc expression to very low mantle zone of the developing hypothalamus where postmitotic levels, leading to hyperphagia and early-onset obesity (17). Inter- neurons are located (Fig. 1A), suggesting that Isl1 expression starts estingly, nPE1 and nPE2 are unrelated sequences with distinct in early postmitotic neurons before terminal differentiation. evolutionary origins; whereas nPE2 is derived from the exaptation Analysis of Isl1 and Pomc expression in the arcuate nucleus of (cooption) of a CORE-short interspersed nuclear element (SINE) adult mice was performed using brain sections of Pomc-EGFP retroposon in the lineage leading to mammals more than 166 mil- transgenic mice (2) to overcome the high background signal that lion years ago (Mya) (18), nPE1 is a placental mammal novelty most mouse monoclonal antibodies yield at this age. Immuno- derived from the exaptation of a LTR-containing a mammalian ap- fluorescence using a rabbit anti-ISL1 antibody showed that ∼86% + parent LTR retroposon that occurred between 150 and 90 Mya (16). of adult Pomc-EGFP neurons coexpress Isl1 (Fig. 1B). The ex- We have recently identified conserved C/ATTA motifs that pression pattern of Isl1 is much broader than that of Pomc in the + might be recognized by homeodomain-containing transcription adult hypothalamus, where only 20% of ISL1 hypothalamic factors (HDTFs) within nPE2 and nPE1, which are essential for neurons coexpress Pomc-EGFP (Fig. 1B). driving reporter gene expression to POMC neurons (17). Because nPE1 and nPE2 are functional
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