Abstract
The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73−/−, p53KO, p53KO;Trp73−/− and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic target.
Highlights
IntroductionReceived 21.10.10; revised 10.11.10; accepted 11.11.10; Edited by G Melino p73 regulates neural progenitor cells (NPC) self-renewal and differentiation Gonzalez-Cano et al family is constituted by the transcription factors p53, p73 and p63
To address whether TP73 ablation affected the biology of embryonic neural progenitor cells (NPC), we used the NS assay.[7,19]
We observed that four times more cells were required to form primary NS from the Trp73À/À neurogenic tissue, than from WT (1/125 cells in WT (0.8%) versus 1/500 cells in Trp73À/À (0.2%), Supplementary Figure 1C), suggesting that lack of p73 produces a depletion of neurosphere-forming cells (NFC) in the neurogenic tissue
Summary
Received 21.10.10; revised 10.11.10; accepted 11.11.10; Edited by G Melino p73 regulates NPC self-renewal and differentiation Gonzalez-Cano et al family is constituted by the transcription factors p53, p73 and p63. We analyzed p73 function in embryonic NPC biology using the NS assay, and demonstrate that p73 is a positive regulator of self-renewal in a p53-independent manner. This self-renewal impairment is later on reflected in a developmental retardation of the neurogenic niches and a significant depletion of the precursor pool of the SVZ and SGZ of P15-Trp73À/À mice, resulting in defective neurogenic niches
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