Mahjoub, M. | Search bioRxiv

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↗

bioRxiv2018

Regulation of Cilia Abundance in Multiciliated Cells

Multiciliated cells (MCC) are specialized epithelia that contain hundreds of motile cilia used to propel fluid over the surface of the cell. To template these cilia, each MCC produces hundreds of centrioles by a process termed centriole amplification. Airway progenitor cells initially contain two parental centrioles that nucleate multiple centrioles at once, and structures called deuterosomes that assemble the vast majority of centrioles during amplification. Remarkably, how each cell regulates the precise number of its centrioles and cilia remains unknown. Here, we investigate mechanisms that establish centriole number in MCC using an ex vivo airway culture model. We show that ablation of parental centrioles, via inhibition of Plk4 kinase, does not perturb deuterosome formation and centriole amplification, nor alter the total complement of centrioles per cell. Airway MCC vary in size and surface area, and exhibit a broad range in centriole number. Quantification of centriole abundance in vitro and in vivo identified a direct relationship between cell-surface area and centriole number. By manipulating cell size and shape, we discovered that centriole number scales with increasing surface area. Collectively, our results demonstrate that parental centrioles and Plk4 are dispensable for deuterosome formation, centriole amplification, and establishment of centriole number. Instead, a cell-intrinsic surface area-dependent mechanism controls centriole and cilia abundance in multiciliated cells.

cell biology↗