Abstract
Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis.
Highlights
In most animal cells, the centrosome is the major microtubule-organizing center (MTOC)
We further demonstrated that various human microcephaly proteins could interact with each other, including CPAP-STIL [9], CPAP-SAS6-CEP135 [10], and RTTN-STIL [11], which are required for building a daughter centriole
Our results show that almost all the RTTN−/−; p53−/− cells (99% ± 1%) exhibited weak and dispersed γ-tubulin (Figure 1A, the quantitation is shown in the right panel) compared to control cells (RTTN+/+; p53+/+ and RTTN+/+; p53−/− cells), in which γ-tubulin was concentrated and focused on the spindle poles, suggesting that RTTN is required for spindle pole integrity in mitosis
Summary
The centrosome is the major microtubule-organizing center (MTOC). It is composed of a pair of centrioles surrounded by pericentriolar material (PCM). Centrioles are barrel-shaped structures composed of microtubules (MTs), and as basal bodies, they serve as a template for the formation of cilia and flagella [1,2,3]. A number of genes that encode centriole/centrosome proteins have been identified as causal genes of MCPH, including MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CPAP/CENPJ, CEP63, and STIL [5]. More than half of microcephaly proteins were found to cooperate with each other and participate in centriole biogenesis and/or centrosome function
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