Sii-Felice Karine, Etienne Olivier, Hoffschir Françoise, Mathieu Céline, Riou Lydia, Barroca Vilma, Haton Céline, Arwert Fré, Fouchet Pierre, Boussin François D, Mouthon Marc-André
CEA, DSV, iRCM, SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France.
EMBO J. 2008 Mar 5;27(5):770-81. doi: 10.1038/emboj.2008.14. Epub 2008 Jan 31.
Although brain development abnormalities and brain cancer predisposition have been reported in some Fanconi patients, the possible role of Fanconi DNA repair pathway during neurogenesis is unclear. We thus addressed the role of fanca and fancg, which are involved in the activation of Fanconi pathway, in neural stem and progenitor cells during brain development and adult neurogenesis. Fanca(-/-) and fancg(-/-) mice presented with microcephalies and a decreased neuronal production in developing cortex and adult brain. Apoptosis of embryonic neural progenitors, but not that of postmitotic neurons, was increased in the neocortex of fanca(-/-) and fancg(-/-) mice and was correlated with chromosomal instability. In adult Fanconi mice, we showed a reduced proliferation of neural progenitor cells related to apoptosis and accentuated neural stem cells exhaustion with ageing. In addition, embryonic and adult Fanconi neural stem cells showed a reduced capacity to self-renew in vitro. Our study demonstrates a critical role for Fanconi pathway in neural stem and progenitor cells during developmental and adult neurogenesis.
尽管在一些范可尼贫血患者中已报道存在脑发育异常和患脑癌倾向，但范可尼贫血DNA修复途径在神经发生过程中的潜在作用尚不清楚。因此，我们研究了参与范可尼贫血途径激活的fanca和fancg在脑发育和成年神经发生过程中对神经干细胞和祖细胞的作用。Fanca(-/-)和fancg(-/-)小鼠出现小头畸形，发育中的皮质和成年大脑中的神经元生成减少。在fanca(-/-)和fancg(-/-)小鼠的新皮质中，胚胎神经祖细胞的凋亡增加，而有丝分裂后神经元的凋亡未增加，且与染色体不稳定性相关。在成年范可尼贫血小鼠中，我们发现神经祖细胞的增殖减少与凋亡有关，并且随着年龄增长神经干细胞耗竭加剧。此外，胚胎和成年范可尼贫血神经干细胞在体外的自我更新能力降低。我们的研究证明了范可尼贫血途径在发育和成年神经发生过程中对神经干细胞和祖细胞起着关键作用。
