The Rfx4 Transcription Factor Modulates Shh Signaling by Regional Control of Ciliogenesis

Abstract

Regulatory factor X (Rfx) homologs regulate the transcription of genes necessary for ciliogenesis in invertebrates and vertebrates. Primary cilia are necessary for Hedgehog signaling and regulation of the activity of the transcriptional regulators known as Gli proteins, which are targets of Hedgehog signaling. Here, we describe an Rfx4(L298P) mouse mutant with distinct dorsoventral patterning defects in the ventral spinal cord and telencephalon due to aberrant Sonic hedgehog (Shh) signaling and Gli3 activity. We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4, and the decrease in its expression in the developing telencephalon and spinal cord of Rfx4(L298P) mutants correlates with defects in patterning and cilia formation. Our data indicate that Rfx4 is a regionally specific transcriptional regulator of ciliogenesis and thus is also a regionally specific modulator of Shh signaling during development of the central nervous system.

Regulatory Factor X Transcription Factors Control Musashi1 Transcription in Mouse Neural Stem/Progenitor Cells

“…L298P has a point mutation in the dimerization domain and shows impaired transcriptional activation ability due to its failure of nuclear localization, as previously reported [29]. As expected, the Rfx4 L298P could not activate the Msi1-6IE reporter compared to wild-type Rfx4 expression (Fig.…”

“…Rfx4 has been reported to be a key regulator of primary cilia development that modulates sonic hedgehog signaling in the neural tube [29,50]. The lack of Rfx4 transcripts or the functional disruption of Rfx4 (Rfx4 L298P ) lead to dorsal midline defects in the forebrain, hydrocephalus, and patterning defects in the telencephalon [28,29]. Because the Msi1 knockout mouse also shows hydrocephalus, there might be a relationship with the phenotype of the Rfx4-disrupted mouse.…”

“…The loss of a Rfx transcription factor known as Daf-19 in Caenorhabditis elegans causes the absence of cilia [47], and Rfx2 and Rfx3 are broadly required for the proper development of cilia in mammals [48,49]. Rfx4 has been reported to be a key regulator of primary cilia development that modulates sonic hedgehog signaling in the neural tube [29,50]. The lack of Rfx4 transcripts or the functional disruption of Rfx4 (Rfx4 L298P ) lead to dorsal midline defects in the forebrain, hydrocephalus, and patterning defects in the telencephalon [28,29].…”

“…Despite these many differences, all Rfx transcription factors except for Rfx6 are highly expressed in brain. The loss of Rfx4 function results in pleiotropic brain defects, and ablation of Rfx3 produced hydrocephalus and abnormal differentiation of ependymal cells [28,29,31]. Knockdown of Rfx7 results in failure of neural tube closure in Xenopus embryos [32].…”

Contrôle transcriptionnel des gènes ciliaires

“…Chez la souris, RFX3 est indispensable à l'élongation des cils du noeud embryonnaire [10] et des cellules des îlots de Langerhans du pancréas endocrine [11], ainsi qu'à la régulation du nombre, de la taille et de la motilité des cils dans les cellules épendymaires [12,13]. D'autre part, les souris déficientes pour Rfx4 présentent des défauts de croissance des cils au niveau du système nerveux central [14]. Chez le poisson zèbre, Rfx2 est nécessaire à l'assemblage des cils de la vésicule de Kupffer, structure impliquée dans la mise en place de l'asymétrie droite/gauche dans cet organisme [15].…”