Abstract
The cilium of a cell translates varied extracellular cues into intracellular signals that control embryonic development and organ function. The dynamic maintenance of ciliary structure and function requires balanced bidirectional cargo transport involving intraflagellar transport (IFT) complexes. IFT172 is a member of the IFT complex B, and IFT172 mutation is associated with pathologies including short rib thoracic dysplasia, retinitis pigmentosa and Bardet-Biedl syndrome, but how it underpins these conditions is not clear. We used the WIM cell line, derived from embryonic fibroblasts of Wimple mice (carrying homozygous Leu1564Pro mutation in Ift172), to probe roles of Ift172 and primary cilia in cell behavior. WIM cells had ablated cilia and deficiencies in directed migration (electrotaxis), cell proliferation and intracellular signaling. Additionally, WIM cells displayed altered cell cycle progression, with increased numbers of chromatids, highlighting dysfunctional centrosome status. Exposure to a physiological electric field promoted a higher percentage of primary cilia in wild-type cells. Interestingly, in situ hybridization revealed an extensive and dynamic expression profile of Ift172 in both developing and adult mouse cortex. In vivo manipulation of Ift172 expression in germinal regions of embryonic mouse brains perturbed neural progenitor proliferation and radial migration of post-mitotic neurons, revealing a regulatory role of Ift172 in cerebral morphogenesis. Our data suggest that Ift172 regulates a range of fundamental biological processes, highlighting the pivotal roles of the primary cilium in cell physiology and brain development.
Highlights
The primary cilium, a microtubule-based structure that acts as the cell’s antenna and signaling hub (Berbari et al, 2009; Veland et al, 2014), originates from the centrosome (Paridaen et al, 2013) and is present on most growth-arrested or differentiated mammalian cells (Gerdes et al, 2009; Baudoin et al, 2012)
Compared to wild type (WT) cells, Wimple mice (WIM) cells did not present any ciliary staining, displaying a complete absence of primary cilia (Figure 1). This highlights the essential roles of IFT172 in ciliary growth and maintenance
WIM cells exhibited a unique spreading growth pattern as they stayed in clumps (Figures 2A,B), suggesting stronger cell-to-cell adhesion or a lack of motility
Summary
The primary cilium, a microtubule-based structure that acts as the cell’s antenna and signaling hub (Berbari et al, 2009; Veland et al, 2014), originates from the centrosome (Paridaen et al, 2013) and is present on most growth-arrested or differentiated mammalian cells (Gerdes et al, 2009; Baudoin et al, 2012). IFT172, Primary Cilia and Corticogenesis the cilium’s structural and functional integrity. Within the central nervous system, cilia are present on both neurons and glia, and their defective function results in various neurociliopathies (Valente et al, 2014) including Bardet-Biedel syndrome (BBS). Intraflagellar Transport 172 (Ift172) is a gene encoding a member of IFT complex B (Follit et al, 2009). There have been case studies linking this gene to growth hormone deficiency (Lucas-Herald et al, 2015; Wit et al, 2016) and BBS (Schaefer et al, 2016), but how IFT172 is involved in these pathologies remains unclear
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