MicroRNA-449 sustains cilia-related networks in the absence of transcription factor TAp73

Motile cilia serve vital functions in development, homeostasis and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory motile multiciliogenesis. Here we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues. Analysis of TAp73-/- animals revealed that TAp73 regulates Foxj1, Rfx2/3, axonemal dyneins Dnali1 and Dnai1, plays a pivotal role in the generation of MCCs in reproductive ducts, and contributes to fertility. However, TAp73 is dispensable for brain MCCs, and robust activity from cilia-related networks is maintained in TAp73-/-. Consistent with TAp73-/-, its target miR34bc was reduced, whereas strong and specific induction of miR449 was observed, along with an increase in E2f4 that induced transcriptional response from miR449 genomic regions. Depletion of both TAp73 and miR449 resulted in defective multiciliogenesis in the brain and hydrocephalus, indicating that miR449 and potentially additional pro-ciliogenic factors cooperate with TAp73 to ensure brain multiciliogenesis and CP development.