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Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.

ABSTRACT: Sonic hedgehog signalling is essential for the embryonic development of many tissues including the central nervous system, where it controls the pattern of cellular differentiation. A genome-wide screen of neural progenitor cells to evaluate the Shh signalling-regulated transcriptome identified the forkhead transcription factor Foxj1. In both chick and mouse Foxj1 is expressed in the ventral midline of the neural tube in cells that make up the floor plate. Consistent with the role of Foxj1 in the formation of long motile cilia, floor plate cells produce cilia that are longer than the primary cilia found elsewhere in the neural tube, and forced expression of Foxj1 in neuroepithelial cells is sufficient to increase cilia length. In addition, the expression of Foxj1 in the neural tube and in an Shh-responsive cell line attenuates intracellular signalling by decreasing the activity of Gli proteins, the transcriptional mediators of Shh signalling. We show that this function of Foxj1 depends on cilia. Nevertheless, floor plate identity and ciliogenesis are unaffected in mouse embryos lacking Foxj1 and we provide evidence that additional transcription factors expressed in the floor plate share overlapping functions with Foxj1. Together, these findings identify a novel mechanism that modifies the cellular response to Shh signalling and reveal morphological and functional features of the amniote floor plate that distinguish these cells from the rest of the neuroepithelium.

SUBMITTER: Cruz C

PROVIDER: S-EPMC2990214 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.

Cruz Catarina C Ribes Vanessa V Kutejova Eva E Cayuso Jordi J Lawson Victoria V Norris Dominic D Stevens Jonathan J Davey Megan M Blight Ken K Bangs Fiona F Mynett Anita A Hirst Elizabeth E Chung Rachel R Balaskas Nikolaos N Brody Steven L SL Marti Elisa E Briscoe James J

Development (Cambridge, England) 20101201 24

Sonic hedgehog signalling is essential for the embryonic development of many tissues including the central nervous system, where it controls the pattern of cellular differentiation. A genome-wide screen of neural progenitor cells to evaluate the Shh signalling-regulated transcriptome identified the forkhead transcription factor Foxj1. In both chick and mouse Foxj1 is expressed in the ventral midline of the neural tube in cells that make up the floor plate. Consistent with the role of Foxj1 in th ...[more]

PMID: 21098568

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Project description:Background:Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer's disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-? (A?) peptide. The A? peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if A? affects primary cilia structure and the Shh signaling cascade. Methods:We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how A? levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted A? as well as synthetic A?. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. Results:Here, we report that APP localizes to primary cilia and A? treatment results in distorted primary cilia structure. In addition, we demonstrate that A? treatment interrupts canonical Shh signal transduction. Conclusions:Overall, our study illustrates that A? can alter primary cilia structure suggesting that elevated A? levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that A? impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics.

Dataset Information

Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.

Publications

Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.

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