Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

Wang, Liheng; Solís, Alain J. De; Goffer, Yossef; Birkenbach, Kathryn E.; Engle, Staci E.; Tanis, Ross; Levenson, Jacob M.; Li, Xueting; Rausch, Richard; Purohit, Manika; Lee, Jen-Yi; Tan, Jerica; Rosa, Maria Caterina De; Doege, Claudia A.; Aaron, Holly L.; Martins, Gabriela J.; Brüning, Jens C.; Egli, Dieter; Costa, Rui M.; Berbari, Nicolas F.; Leibel, Rudolph L.; Stratigopoulos, George

doi:10.1172/jci.insight.123337

Cited by 35 publications

(32 citation statements)

References 78 publications

(112 reference statements)

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“…Consistent with the findings in our cilia mutant models, a POMC-specific congenital deletion of retinitis pigmentosa GTPase regulator-interacting protein-1 like (Rpgrip1l), a ciliary protein that promotes ciliogenesis and mediates periciliary trafficking of leptin receptors, causes hyperphagic obesity 38 . In contrast, adultonset Rpgrip1l depletion in POMC neurons had no effect on body weight 46 . Interestingly, POMC-specific Rpgrip1l mutants displayed enhanced axonal projections to PVH despite a reduction in POMC neuron numbers 46 .…”

Section: Discussionmentioning

confidence: 76%

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

et al. 2020

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Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons.

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Section: Discussionmentioning

confidence: 76%

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

et al. 2020

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“…We then merged peaks with at least 1 bp overlap between replicates to generate a consensus set of peaks. The consensus set peaks were filtered to those which were reproducible in at least half the ATACseq replicates using bedtools intersect 11 . For analyses involving cell-type specific sets of peaks, we considered the set of consensus peaks with mean FPKM value greater than 1 to be "open" in that cell type.…”

Section: Analysis and Peak Callingmentioning

confidence: 99%

“…The majority of GWAS signals reside in non-coding regions of the genome, suggesting that their impact on phenotype is primarily via gene regulation. As cis-acting regulatory elements, such as enhancers or silencers, can act locally or over large genomic distances, the nearest gene to a GWAS signal may not be the principal effector gene [11][12][13][14] . Thus, a major challenge in complex trait genetics is to confidently identify the precise regulatory variant(s) tagged by sentinel SNPs and their corresponding effector target gene(s).…”

Section: Introductionmentioning

confidence: 99%

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

Pahl

Doege

Hodge

et al. 2020

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SummaryThe hypothalamus regulates metabolic homeostasis by influencing behavior, energy utilization and endocrine systems. Given its role governing health-relevant traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function should yield insights into these traits and diseases. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generated a chromatin architecture atlas of an established embryonic stem cell (ESC)-derived hypothalamic-like neuron (HN) model across three stages of in vitro differentiation. We profiled accessible chromatin and identified physically interacting contacts between gene promoters and their putative cis-regulatory elements (cREs) to characterize changes in the gene regulatory landscape during hypothalamic differentiation. Next, we integrated these data with GWAS loci for multiple traits and diseases enriched for heritability in these cells, identifying candidate effector genes and cREs impacting transcription factor binding. Our results reveal common target genes for these traits, potentially identifying core hypothalamic developmental pathways. Our atlas will enable future efforts to determine precise mechanisms underlying hypothalamic development with respect to specific disease pathogenesis.

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“…To determine if the obesity observed in Bbs5 -/mutants was due to a developmental phenotype or a role for Bbs5 in adult homeostasis, we utilized the Bbs5 conditional allele (Bbs5 flox/flox ). Using the near ubiquitously expressed Cagg-Cre ERT2 allele which has produced obesity phenotypes in other ciliopathy alleles, (24,25) we analyzed adult phenotypes upon the conditional loss of BBS5 at P7 and 8 weeks of age. Both male and female conditional mutant Bbs5 D/D animals become obese on breeder chow diet (10% crude fat)…”

Section: Bbs5 Mutant Obesity and Neuronal Ciliamentioning

confidence: 99%

ABbs5mouse model reveals pituitary cilia contributions to developmental abnormalities

Bentley¹,

Engle²,

Haycraft³

et al. 2020

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Primary cilia are critical sensory and signaling compartments present on most mammalian cell types. These specialized structures require a unique signaling protein composition relative to the rest of the cell to carry out their functions. Defects in ciliary structure and signaling result in a broad group of disorders collectively known as ciliopathies. One ciliopathy, Bardet-Biedl Syndrome (BBS; OMIM 209900), presents with diverse clinical features, many of which are attributed to defects in ciliary signaling during both embryonic development and postnatal life. For example, patients exhibit obesity, polydactyly, hypogonadism, developmental delay, and skeletal abnormalities along with sensory and cognitive deficits, but for many of these phenotypes it is uncertain which are developmental in origin. A subset of BBS proteins assembles into the BBSome complex, which is responsible for mediating transport of membrane proteins into and out of the cilium, establishing it as a sensory and signaling hub. Here we describe two new mouse models for BBS resulting from a congenital null and conditional allele of Bbs5. Bbs5 null mice develop a complex phenotype including craniofacial defects, skeletal shortening, ventriculomegaly, infertility, and pituitary anomalies. Utilizing the conditional allele, we show that the male fertility defects, ventriculomegaly, and pituitary abnormalities are only found when Bbs5 is mutated prior to P7 indicating a developmental origin. In contrast, mutation of Bbs5 results in obesity independent of the age of Bbs5 loss. Compared to other animal models of BBS, Bbs5 mutant mice exhibit pathologies that suggest a specialized role for Bbs5 in ciliary function.

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Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

Cited by 35 publications

References 78 publications

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

ABbs5mouse model reveals pituitary cilia contributions to developmental abnormalities

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