Dataset Information

The ciliopathy gene Rpgrip1l is essential for hair follicle development.

ABSTRACT: The primary cilium is essential for skin morphogenesis through regulating the Notch, Wnt, and hedgehog signaling pathways. Prior studies on the functions of primary cilia in the skin were based on the investigations of genes that are essential for cilium formation. However, none of these ciliogenic genes has been linked to ciliopathy, a group of disorders caused by abnormal formation or function of cilia. To determine whether there is a genetic and molecular link between ciliopathies and skin morphogenesis, we investigated the role of RPGRIP1L, a gene mutated in Joubert (JBTS) and Meckel (MKS) syndromes, two severe forms of ciliopathy, in the context of skin development. We found that RPGRIP1L is essential for hair follicle morphogenesis. Specifically, disrupting the Rpgrip1l gene in mice resulted in reduced proliferation and differentiation of follicular keratinocytes, leading to hair follicle developmental defects. These defects were associated with significantly decreased primary cilium formation and attenuated hedgehog signaling. In contrast, we found that hair follicle induction and polarization and the development of interfollicular epidermis were unaffected. This study indicates that RPGRIP1L, a ciliopathy gene, is essential for hair follicle morphogenesis likely through regulating primary cilia formation and the hedgehog signaling pathway.

SUBMITTER: Chen J

PROVIDER: S-EPMC4340706 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The ciliopathy gene Rpgrip1l is essential for hair follicle development.

Chen Jiang J Laclef Christine C Moncayo Alejandra A Snedecor Elizabeth R ER Yang Ning N Li Li L Takemaru Ken-Ichi KI Paus Ralf R Schneider-Maunoury Sylvie S Clark Richard A RA

The Journal of investigative dermatology 20141114 3

The primary cilium is essential for skin morphogenesis through regulating the Notch, Wnt, and hedgehog signaling pathways. Prior studies on the functions of primary cilia in the skin were based on the investigations of genes that are essential for cilium formation. However, none of these ciliogenic genes has been linked to ciliopathy, a group of disorders caused by abnormal formation or function of cilia. To determine whether there is a genetic and molecular link between ciliopathies and skin mo ...[more]

PMID: 25398052

Similar Datasets

Project description:Primary cilia are essential for CNS development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rpgrip1l ciliopathy gene is disrupted. At the end of gestation, Ftm -/- fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm -/- embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. In Ftm -/- embryos, Sonic hedgehog (Shh) expression was virtually lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. Gli activity was severely downregulated but not lost in the ventral forebrain and in regions adjacent to the Shh-expressing ZLI. Reintroduction of the repressor form of Gli3 into the Ftm -/- background restored optic cup formation. Our data thus uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects.SIGNIFICANCE STATEMENT The Hedgehog (Hh) signaling pathway is essential for proper forebrain development as illustrated by a human condition called holoprosencephaly. The Hh pathway relies on primary cilia, cellular organelles that receive and transduce extracellular signals and whose dysfunctions lead to rare inherited diseases called ciliopathies. To date, the role of cilia in the forebrain has been poorly studied outside the telencephalon. In this paper we study the role of the Ftm/Rpgrip1l ciliopathy gene in mouse forebrain development. We uncover complex functions of primary cilia in forebrain morphogenesis through region-specific modulation of the Hh pathway. Our data call for further examination of forebrain defects in ciliopathies and for a search for ciliopathy genes as modifiers in human conditions affecting forebrain development.

Project description:BACKGROUND:Cultured epidermal stem cells (Epi-SCs) and skin-derived precursors (SKPs) were capable of reconstituting functional hair follicles after implantation, while the signaling pathways that regulate neogenic hair follicle formation are poorly investigated. In this study, we aimed to understand the interactions between Epi-SCs and SKPs during skin organoid formation and to uncover key signal pathways crucial for de novo hair follicle regeneration. METHODS:To track their fate after transplantation, Epi-SCs derived from neonatal C57BL/6 mice were labeled with tdTomato, and SKPs were isolated from neonatal C57BL/6/GFP mice. A mixture of Epi-SCs-tdTomato and SKPs-EGFP in Matrigel was observed under two-photon microscope in culture and after implantation into excisional wounds in nude mice, to observe dynamic migrations of the cells during hair follicle morphogenesis. Signaling communications between the two cell populations were examined by RNA-Seq analysis. Potential signaling pathways revealed by the analysis were validated by targeting the pathways using specific inhibitors to observe a functional loss in de novo hair follicle formation. RESULTS:Two-photon microscopy analysis indicated that when Epi-SCs and SKPs were mixed in Matrigel and cultured, they underwent dynamic migrations resulting in the formation of a bilayer skin-like structure (skin organoid), where Epi-SCs positioned themselves in the outer layer; when the mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, a bilayer structure resembling the epidermis and the dermis formed at the 5th day, and de novo hair follicles generated subsequently. RNA-Seq analysis of the two cell types after incubation in mixture revealed dramatic alterations in gene transcriptome, where PI3K-Akt signaling pathway in Epi-SCs was significantly upregulated; meanwhile, elevated expressions of several growth factors and cytokine potentially activating PI3K were found in SKPs, suggesting active reciprocal communications between them. In addition, inhibition of PI3K or Akt by specific inhibitors markedly suppressed the hair follicle regeneration mediated by Epi-SCs and SKPs. CONCLUSIONS:Our data indicate that the PI3K-Akt signaling pathway plays a crucial role in de novo hair follicle regeneration, and the finding may suggest potential therapeutic applications in enhancing hair regeneration.

Dataset Information

The ciliopathy gene Rpgrip1l is essential for hair follicle development.

Publications

The ciliopathy gene Rpgrip1l is essential for hair follicle development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets