GEMC1-MCIDAS transcriptional program regulates multiciliogenesis in the choroid plexus and acts as a barrier to tumorigenesis

Abstract

Multiciliated cells (MCCs) in the brain include the ependymal cells and choroid plexus (CP) epithelial cells. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. However, the mechanisms and functional significance of multiciliogenesis in the CP remain unknown. Deregulated oncogenic signals cause CP carcinoma (CPC), a rare but aggressive pediatric brain cancer. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. NOTCH-driven CP tumors were monociliated, whereas disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of GEMC1 and MCIDAS, early regulators of multiciliogenesis. Consistently, GEMC1-MCIDAS function is essential for multiciliation in the CP, and is critical for correcting multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia. Consistently, CPC driven by deletion of Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal a GEMC1-MCIDAS multiciliation program in the CP critical for inhibiting tumorigenesis, and it may have therapeutic implications for the treatment of CPC.

Diversity and Function of Motile Ciliated Cell Types within Ependymal Lineages of the Zebrafish Brain

“…This contrasts with mouse ependymal cells where loss of Gmnc/Gemc1 completely abolishes ciliogenesis, and prevents the maturation of ependymal cells [57,58] and MCCs of the ChP [80]. Thus, ciliary defects in the gmnc mutant zebrafish brain resembles more closely the phenotype of Mcidas knockout mice, where multiciliated precursor cells are still specified, but do not acquire multiciliation and instead generate a single motilelike cilium [55,80]. These results are also similar to our earlier report of gmnc loss-of-function in the zebrafish embryonic kidneys where MCC precursors differentiate with single motile cilia [59].…”

“…Upon loss of the central regulator of multiciliation, gmnc, we found that zebrafish ependymal MCCs differentiate a single cilium, implying that Gmnc activity does not impact motile ciliogenesis per se but only the process of multiciliation. This contrasts with mouse ependymal cells where loss of Gmnc/Gemc1 completely abolishes ciliogenesis, and prevents the maturation of ependymal cells [57,58] and MCCs of the ChP [80]. Thus, ciliary defects in the gmnc mutant zebrafish brain resembles more closely the phenotype of Mcidas knockout mice, where multiciliated precursor cells are still specified, but do not acquire multiciliation and instead generate a single motilelike cilium [55,80].…”

“…These different configurations may result from the eversion of the neural tube in the zebrafish, in contrast to evagination of the mammalian brain [47], and the necessity to increase the surface area of the ependymal layer with limited space. Similar to the zebrafish, cells of the mammalian ChP are multiciliated [80,88,89] and express Foxj1 [80,90]. Cilia on the mouse ChP have also been shown to be motile, particularly at the perinatal period [89,91,92].…”

Diversity and function of motile ciliated cell types within ependymal lineages of the zebrafish brain

“…ciliogenesis, per se, but only the process of multiciliation. This contrasts with mouse ependymal cells, where loss of Gmnc/ Gemc1 completely abolishes ciliogenesis and prevents the maturation of ependymal cells (Kyrousi et al, 2015;Terré et al, 2016) and MCCs of the ChP (Li et al, 2020). Thus, ciliary defects in the gmnc mutant zebrafish brain resembles more closely the phenotype of Mcidas knockout mice, where multiciliated precursor cells are still specified but generate a single motile-like cilium (Lu et al, 2019;Li et al, 2020).…”

“…This raises the question as to why foxj1a is needed later in development in this population of cells. It is possible that foxj1a is expressed because Gmnc eventually induces the expression of both Foxj1 orthologs ( Zhou et al., 2015 ; Stubbs et al., 2012 ; Chong et al., 2018 ; Terré et al., 2016 ; Arbi et al., 2016 ; Kyrousi et al., 2015 ; Li et al., 2020 ) without discriminating between them. Alternatively, MCCs could require both foxj1 genes to transcribe enough motile cilia-specific gene transcripts for multiciliation.…”