Retrieved evidence partially points to cortical neurogenesis occurring in centriole-depleted models when p53 is removed, but does not directly establish that mature neurons divide in the absence of centrioles.
Abstract Olfaction in most animals is mediated by neurons bearing cilia that are accessible to the environment. Olfactory sensory neurons (OSNs) in chordates usually have multiple cilia, each with a centriole at its base. OSNs differentiate from stem cells in the olfactory epithelium, and how the epithelium generates cells with many centrioles—about 16 in mouse—is not yet understood. We show that centrioles are amplified via centriole rosette formation in both embryonic development and turnover of the olfactory epithelium in adults, and rosette-bearing cells often have free centrioles in addition. Cells with amplified centrioles can go on to divide, with centrioles clustered at each pole. Additionally, we found that immediate neuronal precursors amplify centrioles concomitantly with elevation of mRNA for Plk4 and Stil, key regulators of centriole duplication. Our findings highlight the importance of accounting for centriole amplification in neuron regeneration therapies derived from olfactory epithelia.
ean ± SD. Individual p values and degrees of freedom are available in the Supplementary Methods Checklist. Because the cortex develops in a birth date-dependent inside-out sequence, in which neurons born at later times migrate past earlier-born neurons and occupy superficial positions 12 , we examined the identity of neurons that were lost in the Sas-4 −/− cortex. Compared with the WT control, the number of early-born CTIP2-expressing deep layer neurons 28 was not significantly changed, but the number of late-born CUX1-expressing superficial layer neurons 28 was reduced by ~41% in the Sas-4 −/− cortex ( Fig. 2c–e ). The preferential loss of the superficial, but not deep, layer neurons most probably reflects the progressive loss of centrioles and appearance of apoptotic cells upon SAS-4 removal ( Fig. 1c–j ); that is, apoptosis mostly occurs when the superficial layer neurons are produced. Moreover, the neuronal loss and microcephaly in Sas-4 −/− mice were not due to a loss of primary cilia, as there was no detectable apoptosis, neuronal loss or microcephaly in the conditional Ift88 −/− brain that lacked primary cilia ( Supplementary Fig. 4 ).
Remarkably, removal of p53 completely restored the superficial layer neurons lost in the Sas-4 −/− cortex. The thickness and cell number of the superficial layers marked by CUX1 in the Sas-4 −/− p53 −/− cortex were not significantly different from those of the WT control at P1 ( Fig. 2c–e ) and P14 ( Fig. 2g–i ). These results suggest that Sas-4 −/− cells in the developing cortex retain the ability to generate the correct number and type of neurons if they are rescued from apoptosis by removal of p53. Notably, we observed a minor but significant population of CUX1-expressing neurons located in the deep layers ( Fig. 2g arrow and Supplementary Fig. 5a ) as well as a small heterotopia in the posterior dorsomedial region of the Sas-4 −/− p53 −/− cortex ( Supplementary Fig. 6 ), indicating subtle defects in cortical neuronal migrat
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