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Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development.

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.

SUBMITTER: Pruski M

PROVIDER: S-EPMC6890611 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development.

Pruski Michal M Hu Ling L Yang Cuiping C Wang Yubing Y Zhang Jin-Bao JB Zhang Lei L Huang Ying Y Rajnicek Ann M AM St Clair David D McCaig Colin D CD Lang Bing B Ding Yu-Qiang YQ

Frontiers in cell and developmental biology 20191126

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 t ...[more]

PMID: 31850339

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Project description:UnlabelledBackgroundThe primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the past several years a plethora of papers has indicated a crucial role for primary cilia in the development of a wide variety of organs. We have investigated heart development in cobblestone, a hypomorphic allele of the gene encoding the intraflagellar transport protein Ift88, and uncovered a number of the most common congenital heart defects seen in newborn humans.MethodsWe generated serial sections of mutant cobblestone and wild type embryos in the region encompassing the heart and the cardiac outflow tract. The sections were further processed to generate three-dimensional reconstructions of these structures, and immunofluorescence confocal microscopy, transmission electron microscopy, and in situ hybridization were used to examine signal transduction pathways in the relevant areas. Whole mount in situ hybridization was also employed for certain developmental markers.ResultsIn addition to an enlarged pericardium and failure of both ventricular and atrial septum formation, the cobblestone mutants displayed manifold defects in outflow tract formation, including persistent truncus arteriosus, an overriding aorta, and abnormal transformation of the aortic arches. To discern the basis of these anomalies we examined both the maintenance of primary cilia as well as endogenous and migratory embryonic cell populations that contribute to the outflow tract and atrioventricular septa. The colonization of the embryonic heart by cardiac neural crest occurred normally in the cobblestone mutant, as did the expression of Sonic hedgehog. However, with the loss of primary cilia in the mutant hearts, there was a loss of both downstream Sonic hedgehog signaling and of Islet 1 expression in the second heart field, a derivative of the pharyngeal mesoderm. In addition, defects were recorded in development of atrial laterality and ventricular myocardiogenesis. Finally, we observed a reduction in expression of Bmp4 in the outflow tract, and complete loss of expression of both Bmp2 and Bmp4 in the atrioventricular endocardial cushions. Loss of BMP2/4 signaling may result in the observed proliferative defect in the endocardial cushions, which give rise to both the atrioventricular septa as well as to the septation of the outflow tract.ConclusionsTaken together, our results potentially identify a novel link between Sonic hedgehog signaling at the primary cilium and BMP-dependent effects upon cardiogenesis. Our data further point to a potential linkage of atrioventricular septal defects, the most common congenital heart defects, to genes of the transport machinery or basal body of the cilia.

Project description:The primary cilium is a microtubule-based and nonmotile organelle functioning as a cellular antenna that is involved in the regulation of cell proliferation, differentiation, and migration. In breast cancer cells, the primary cilium is a structure that decreases in incidence with increasing degrees of transformation and may be biologically more important in estrogen receptor (ER?)-negative breast cancer cells. Split ends (SPEN) is an ER? corepressor that we have identified as a tumor suppressor protein in ER?-positive breast cancer cells whose hormone-independent roles in breast cancer have never been explored.We determined the hormone-independent transcriptional program regulated by the ER? cofactor SPEN in breast cancer using DNA microarrays. The biological functions regulated by SPEN independently of hormones were studied in vitro in ER?-positive and ER?-negative breast cancer cells. Finally, we examined the clinical relevance of SPEN expression in cohorts of breast cancer samples with outcome data.We found that SPEN is coexpressed with a number of genes involved in ciliary biology, including the ciliogenic transcription factor RFX3, in a hormone-independent manner. SPEN reexpression in T47D cells containing a nonsense mutation in SPEN restored the primary cilium, whereas its knockdown in MCF10A and Hs578T cells considerably decreased primary cilia levels. We also report that SPEN regulates migration in breast cells, but only in those harboring primary cilia, and that KIF3A silencing, a critical factor in primary cilia, partially reverses SPEN's effects, suggesting that SPEN may coordinate cellular movement through primary cilia-dependent mechanisms. Finally, we found that high SPEN RNA levels were predictive of early metastasis in two independent cohorts of 77 (HR 2.25, P?=?0.03) and 170 (HR?=?2.23, P?=?0.004) patients with ER?-negative breast cancer.Together, our data demonstrate a role for SPEN in the regulation of primary cilia formation and cell migration in breast cancer cells, which may collectively explain why its expression is associated with time to metastasis in cohorts of patients with ER?-negative breast cancers.

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Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development.

Publications

Roles for IFT172 and Primary Cilia in Cell Migration, Cell Division, and Neocortex Development.

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