Ttc21b is required for proper proliferation of neural progenitor cells.

Primary cilia play a pivotal role in cellular signaling and development. Human primary microcephaly is strongly associated with pathogenic variants in primary cilia genes. Here, we examine the role of Ttc21b, a component of the intraflagellar transport-A complex, during mouse forebrain development by using a Ttc21balien null allele. Our findings reveal that significant microcephaly in homozygous mutants is caused by disrupted neural progenitor proliferation and differentiation. Histological and immunohistochemical analyses show an enlarged ventricular zone and reduced cortical plate thickness accompanied by altered mitotic spindle angles, suggesting defects in symmetric versus asymmetric cell divisions. Embryonic expression patterns suggest that perdurant TTC21B protein underlies these phenotypes. Progenitor proliferation kinetics were disrupted along with changes in TBR2-positive intermediate progenitors and TBR1-positive early-developing neurons. Neuronal processes in the cortical plate were significantly shortened. Our findings support a model in which early expression of Ttc21b in neural precursor cells destined for the forebrain is critical to ensure TTC21B protein levels to sustain subsequent neural progenitor proliferation and differentiation. These results advance our understanding of the role primary cilia have in cortical development.