Wang, Liheng, De Solis, Alain J., Gaffer, Yossef, Birkenbach, Kathryn E., Engle, Staci E., Tanis, Ross, Levenson, Jacob M., Li, Xueting, Rausch, Richard, Purohit, Manika, Lee, Jen-Yi, De Rosa, Maria Caterina, Doege, Claudia A., Aaron, Holly L., Martins, Gabriela J., Bruening, Jens C., Egli, Dieter, Costa, Rui, Berbari, Nicolas, Leibel, Rudolph L. and Stratigopoulos, George ORCID: 0000-0003-4752-9123 (2019). Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development. JCI Insight, 4 (3). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

Full text not available from this repository.

Abstract

Intronic polymorphisms in the a-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/ Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wang, LihengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Solis, Alain J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaffer, YossefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Birkenbach, Kathryn E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engle, Staci E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tanis, RossUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Levenson, Jacob M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, XuetingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rausch, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Purohit, ManikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Jen-YiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Rosa, Maria CaterinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doege, Claudia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aaron, Holly L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martins, Gabriela J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Egli, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costa, RuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berbari, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leibel, Rudolph L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stratigopoulos, GeorgeUNSPECIFIEDorcid.org/0000-0003-4752-9123UNSPECIFIED
URN: urn:nbn:de:hbz:38-156858
DOI: 10.1172/jci.insight.123337
Journal or Publication Title: JCI Insight
Volume: 4
Number: 3
Date: 2019
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; BASAL BODY PROTEIN; FTO GENE; JOUBERT SYNDROME; TRANSITION ZONE; ENERGY-INTAKE; FOOD-INTAKE; OBESITY; EXPRESSION; VARIANTSMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15685

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item