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 Rpgril1 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.

Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

“…S9B). These cells are proposed to be keratinocytes that are committed to the follicular fate but have failed to develop into hair follicles because of disrupted Hh signaling or primary cilia formation (Chen et al, 2015;Chiang et al, 1999;Dai et al, 2013Dai et al, , 2011Gat et al, 1998;Mill et al, 2003;St-Jacques et al, 1998). Thus, the congregation of these ciliated keratinocytes in the epidermal invaginations of Ift27 −/− skin transplants not only confirmed this speculation but also strengthened our previous observation that Ift27 is essential for Hh signaling (Fig.…”

“…Interestingly, when Hh or ciliary genes were disrupted in a tissue-specific fashion, i.e. in the epidermal lineage (Dai et al, 2013) or in mesenchymal cells (Lehman et al, 2009;Woo et al, 2012), the resultant phenotypes were almost identical to those in germline mutants (Chen et al, 2015;Chiang et al, 1999;Dai et al, 2011;Gat et al, 1998;Mill et al, 2003;St-Jacques et al, 1998;Woo et al, 2012). These findings strongly suggest that disrupting Hh signaling or cilia formation/function in either or both tissue compartments of the hair follicle will, individually or collectively, contribute to hair follicle morphogenesis defects.…”

“…In addition, the primary cilium is essential for the proteolytic processing of Gli factors into transcriptional repressors in the absence of the ligand (Haycraft et al, 2005;Huangfu and Anderson, 2005). A number of recent studies demonstrated that disrupting cilia formation results in developmental arrest of hair follicles by suppressing Hh signaling (Chen et al, 2015;Dai et al, 2013Dai et al, , 2011Lehman et al, 2009). These studies confirmed the integral role of primary cilia in mediating the epithelial-mesenchymal crosstalk required for hair follicle morphogenesis.…”

“…The hair follicle phenotype observed in the germline mutant Ift27 −/− mice is reminiscent of that previously reported for Hh and primary cilia germline mutants (Chen et al, 2015;Chiang et al, 1999;Dai et al, 2011;Gat et al, 1998;Mill et al, 2003;St-Jacques et al, 1998;Woo et al, 2012). Interestingly, when Hh or ciliary genes were disrupted in a tissue-specific fashion, i.e.…”

“…Activation of the Hh signaling pathway requires the primary cilia. A number of recent studies unequivocally demonstrated that the primary cilium is essential for hair follicle morphogenesis; disrupting ciliogenesis results in the arrest of hair follicle development due to disrupted Hh signaling (Chen et al, 2015;Dai et al, 2013Dai et al, , 2011Lehman et al, 2009). Thus, the formation of the ciliary axoneme is prerequisite for its function; disrupting cilia formation inevitably disrupts its function, including the transduction of Hh signals.…”