Biology subjects

Terre, B.

Publications and source records attributed to Terre, B..

3 recordsLinked to original sources

bioRxiv2022

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.

cell biology↗

bioRxiv2020

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

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.

cancer biology↗

bioRxiv2018

GEMC1 and CCNO are required for efferent duct development and male fertility

GEMC1 is a Geminin family protein that triggers the E2F4/5-mediated transcriptional activation of target genes, including many required for multiciliogenesis, such as Mcidas, FoxJ1 and Ccno. Male mice lacking either Gemc1 or Ccno were found to be infertile, but the origin of this defect has remained unclear. Here we show that mice lacking either Gemc1 or Ccno showed a nearly empty seminiferous tubule phenotype. While both genes were expressed in the testes, much higher levels were observed in the efferent ducts that mobilize sperm to the epididymis. We found that both GEMC1 and CCNO were required for the generation of multiciliated cells in the efferent ducts but that they differentially affect activation of FoxJ1 and Tp73. These data indicate that defective efferent duct development, rather than defects in testes development, are likely the primary origin of male infertility observed in the absence of GEMC1 and CCNO and this could extend to Reduced Generation of Multiple Motile Cilia patients with MCIDAS and CCNO mutations.\n\nSummary statementWe demonstrate that male mice lacking GEMC1 or CCNO are infertile due to defects in the formation of the efferent ducts.

developmental biology↗