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.

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

“…However, it significantly restored cilia length in DFC ) and embryos overexpressing Dkk1 (P<1.83ϫ10 -10 ) (Fig. 3I), which is in agreement with the documented role of foxj1a in cilia length elongation (Cruz et al, 2010;Yu et al, 2011). To a lesser extent, ectopic expression of foxj1a RNA enhanced cilia number in DFC fzd10 MO embryos (from 18±7 to 25±8; P<0.02), DFC -catenin1 MO embryos (P<0.04) and embryos with activated Dkk1 (P<0.15) (Fig.…”

“…Are there other transcription factors that can compensate for the loss of Foxj1? For example, normal ciliogenesis in the FP of Foxj1-null mice was attributed to redundant functions of Rfx3 (regulatory factor binding to the X box), a protein important for cilia biosynthesis and cilia motility (Bonnafe et al, Zein et al, 2009;Cruz et al, 2010). It would be interesting to know whether Rfx3 has a similar redundant function in the node.…”

Differential regulation of node formation, nodal ciliogenesis and cilia positioning by Noto and Foxj1

“…Thus, in node cells there appears to be a clear epistatic relationship between Foxj1 and Rfx3, with Foxj1 acting upstream of Rfx3. This differs from cultured multiciliated mouse ependymal cells, in which RFX3 regulated Foxj1 expression (El Zein et al, 2009), and from mouse floorplate cells, in which expression of Rfx3 was unaffected by the loss of Foxj1 (Cruz et al, 2010). Thus, the regulatory relationship between these two transcription factors that govern ciliogenesis appears to differ between the node and other tissues.…”

“…Thus, the regulatory relationship between these two transcription factors that govern ciliogenesis appears to differ between the node and other tissues. It is noteworthy that ectopic expression of Foxj1 in neural progenitors converted short primary cilia into long cilia, but in Foxj1 mutant floorplate cells cilia length was unaffected, which was attributed to redundant functions of Rfx3 and Foxj1 (Cruz et al, 2010). In cultured mouse ependymal cells, loss of Rfx3 function led to reduced growth of motile cilia and affected expression of genes involved in cilia assembly and motility (El Zein et al, 2009).…”

Contrôle transcriptionnel des gènes ciliaires

“…Des expé-riences réalisées chez la souris, le poisson zèbre et dans les cellules respiratoires humaines, montrent que FOXJ1 induit l'expression des gènes RFX3 et RFX2 pendant la différen-ciation des cils mobiles [24,26,32]. Cependant, Rfx3 ne semble pas être régulé par FOXJ1 dans le plancher du tube neural, qui porte de longs monocils dont la fonction est encore débattue [33]. À l'inverse, dans les cellules épen-dymaires de souris, RFX3 se lie au promoteur du gène Foxj1 [12], suggérant l'existence d'une régulation croisée entre ces facteurs de transcription.…”