Positive selection of co-opted mobile genetic elements in a mammalian gene: If you can't beat them, join them (original) (raw)
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Molecular and Cellular Biology, 2005
The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-offunction mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a highly significant quantitative trait locus on chromosome 2 associated with obesity traits in several human populations. Here, we identify two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of mammalian POMC transcriptional units. We show that mouse or human genomic regions containing these enhancers are able to direct reporter gene expression to POMC hypothalamic neurons, but not the pituitary of transgenic mice. Conversely, deletion of nPE1 and nPE2 in the context of the entire transcriptional unit of POMC abolishes transgene expression in the hypothalamus without affecting pituitary expression. Our results indicate that the nPEs are necessary and sufficient for hypothalamic POMC expression and that POMC expression in the brain and pituitary is controlled by independent sets of enhancers. Our study advances the understanding of the molecular nature of hypothalamic POMC neurons and will be useful to determine whether polymorphisms in POMC regulatory regions play a role in the predisposition to obesity.
PLoS Genetics, 2007
The proopiomelanocortin gene (POMC) is expressed in the pituitary gland and the ventral hypothalamus of all jawed vertebrates, producing several bioactive peptides that function as peripheral hormones or central neuropeptides, respectively. We have recently determined that mouse and human POMC expression in the hypothalamus is conferred by the action of two 59 distal and unrelated enhancers, nPE1 and nPE2. To investigate the evolutionary origin of the neuronal enhancer nPE2, we searched available vertebrate genome databases and determined that nPE2 is a highly conserved element in placentals, marsupials, and monotremes, whereas it is absent in nonmammalian vertebrates. Following an in silico paleogenomic strategy based on genome-wide searches for paralog sequences, we discovered that opossum and wallaby nPE2 sequences are highly similar to members of the superfamily of CORE-short interspersed nucleotide element (SINE) retroposons, in particular to MAR1 retroposons that are widely present in marsupial genomes. Thus, the neuronal enhancer nPE2 originated from the exaptation of a CORE-SINE retroposon in the lineage leading to mammals and remained under purifying selection in all mammalian orders for the last 170 million years. Expression studies performed in transgenic mice showed that two nonadjacent nPE2 subregions are essential to drive reporter gene expression into POMC hypothalamic neurons, providing the first functional example of an exapted enhancer derived from an ancient CORE-SINE retroposon. In addition, we found that this CORE-SINE family of retroposons is likely to still be active in American and Australian marsupial genomes and that several highly conserved exonic, intronic and intergenic sequences in the human genome originated from the exaptation of CORE-SINE retroposons. Together, our results provide clear evidence of the functional novelties that transposed elements contributed to their host genomes throughout evolution. Citation: Santangelo AM, de Souza FSJ, Franchini LF, Bumaschny VF, Low MJ, et al. (2007) Ancient exaptation of a CORE-SINE retroposon into a highly conserved mammalian neuronal enhancer of the proopiomelanocortin gene. PLoS Genet 3(10): e166
F1000 - Post-publication peer review of the biomedical literature, 2010
Hypothalamic circuits regulating energy balance are highly plastic and develop in response to nutrient and hormonal cues. To identify processes that could be susceptible to gestational influences in the mouse, we characterized the ontogeny of proopiomelanocortin (POMC) and neuropeptide Y (NPY) populations, which exert opposing influences on food intake and body weight. These analyses revealed that Pomc is broadly expressed in immature hypothalamic neurons and that half of embryonic Pomc-expressing precursors subsequently adopt a non-POMC fate in the adult. Moreover, nearly one quarter of the mature orexigenic NPY population shares a common progenitor with anorexigenic POMC neurons.
Molecular Endocrinology, 2007
The stress response involves complex physiological mechanisms that maximize behavioral efficacy during attack or defense and is highly conserved in all vertebrates. Key mediators of the stress response are pituitary hormones encoded by the proopiomelanocortin gene (POMC). Despite conservation of physiological function and expression pattern of POMC in all vertebrates, phylogenetic footprinting analyses at the POMC locus across vertebrates failed to detect conserved noncoding sequences with potential regulatory function. To investigate whether ortholog POMC promoters from extremely distant vertebrates are functionally conserved, we used 5-flanking sequences of the teleost fish Tetraodon nigroviridis POMC␣ gene to produce transgenic mice. Tetraodon POMC␣ promoter targeted reporter gene expression exclusively to mouse pituitary cells that normally express Pomc. Importantly, transgenic expression in mouse corticotrophs was increased after adrenalectomy. To understand how conservation of precise gene expression mechanisms coexists with great sequence divergence, we investigated whether very short elements are still conserved in all vertebrate POMC promoters. Multiple local sequence alignments that consider phylogenetic relationships of ortholog regions identified a unique 10-bp motif GTGCTAA(T/G)CC that is usually present in two copies in POMC 5-flanking sequences of all vertebrates. Underlined nucleotides represent totally conserved sequences. Deletion of these paired motifs from Tetraodon POMC␣ promoter markedly reduced its transcriptional activity in a mouse corticotropic cell line and in pituitary POMC cells of transgenic mice. In mammals, the conserved motifs correspond to reported binding sites for pituitary-specific nuclear proteins that participate in POMC transcriptional regulation. Together, these results demonstrate that mechanisms that participate in pituitary-specific and hormonally regulated expression of POMC have been preserved since mammals and teleosts diverged from a common ancestor 450 million years ago despite great promoter sequence divergence. (Molecular Endocrinology 21: [2738][2739][2740][2741][2742][2743][2744][2745][2746][2747][2748][2749] 2007) T HE PROOPIOMELANOCORTIN GENE (POMC) encodes a prohormone that gives rise to several bioactive peptides including ACTH, the melanocortins ␣-, -, and ␥-MSH, and the opioid peptide -endor-phin. POMC is mainly transcribed in discrete populations of brain neurons and in the pituitary gland, where it is expressed in melanotrophs of the intermediate lobe and corticotrophs of the anterior lobe. ACTH is a principal component of the hypothalamic-pituitary-adrenal (HPA) axis that mediates the stress response in all vertebrates (1-3). Stress-induced release of the hypothalamic peptide CRH stimulates the release of ACTH from pituitary corticotrophs, which in turn promotes glucocorticoid release from the adrenal gland cortex. As part of a negative feedback loop, glucocorticoids decrease the expression of CRH in the hypothalamus and POMC in pituitary corticotrophs. The crucial importance of ACTH in the stress response can be appreciated in humans carrying mutations that inactivate the POMC gene, who die from adrenal insufficiency unless permanently supplemented with glu-
PLoS genetics, 2015
Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low leve...
European Journal of Pharmacology, 2011
The gene encoding the prohormone proopiomelanocortin (POMC) is mainly expressed in two regions in vertebrates, namely corticotrophs and melanotrophs in the pituitary and a small population of neurons in the arcuate nucleus of the hypothalamus. In this latter region, POMCderived peptides participate in the control of energy balance and sensitivity to pain. Neuronal expression of POMC is conferred by two enhancers, nPE1 and nPE2, which are conserved in most mammals, but no transcription factors are yet known to bind to these enhancers. In this work, by means of a one-hybrid screening, we identify that nPE2 possesses an element recognized by transcription factors of the nuclear receptor superfamily. This element, named NRBE, is conserved in all known nPE2 enhancers and is necessary to confer full enhancer strength to nPE2-driven reporter gene expression in transgenic mice assays, indicating that the phylogenetic conservation of the element is indicative of its functional importance. In a search for candidate nuclear receptors that might control POMC we observed that estrogen receptor alpha (ESR1)-a known regulator of energy balance at the hypothalamic level-can bind to the NRBE element in vitro. In addition we observed by immunofluorescence that ESR1 is coexpressed with POMC in around 25-30% of hypothalamic neurons of males and females during late embryonic stages and adulthood. Thus, our results indicate that hypothalamic expression of POMC is controlled by nuclear receptors and establish ESR1 as a candidate regulator of POMC.
Molecular design of hypothalamus development
Nature, 2020
A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs 1,2. Nevertheless, a developmental blueprint integrating molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development remains unresolved 3. Here, we combine single-cell RNA-seq on 51,199 cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with GWAS-based disease phenotyping and genetic lineage reconstruction to show that 9 glial and 33 neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes arising from neurotransmitters, neuropeptides and transcription Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Developmental Biology, 2011
The neuroendocrine hypothalamus regulates a spectrum of essential biological processes and underlies a range of diseases from growth failure to obesity. While the exploration of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, very little is known about the processes underlying the genesis and specification of the neurons in the arcuate and ventromedial nuclei. Recent studies demonstrate that the proneural basic helix-loop-helix transcription factor Mash1 is required for neurogenesis and neuronal subtype specification in the ventral hypothalamus. We demonstrate here that Ngn3, another basic helix-loop-helix transcription factor, is expressed in mitotic progenitors in the arcuate and ventromedial hypothalamic regions of mouse embryos from embryonic days 9.5-17.5. Genetic fate mapping and loss of function studies in mice demonstrate that Ngn3+ progenitors contribute to subsets of POMC, NPY, TH and SF1 neurons and is required for the specification of these neuronal subtypes in the ventral hypothalamus. Interestingly, while Ngn3 promotes the development of arcuate POMC and ventromedial SF1 neurons, it inhibits the development of NPY and TH neurons in the arcuate nuclei. Given the opposing roles of POMC and NPY neurons in regulating food intake, these results indicate that Ngn3 plays a central role in the generation of neuronal populations controlling energy homeostasis in mice.