p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis

Talos, Flaminia; Abraham, A. Johnston; Vaseva, Angelina V.; Holembowski, Lena; Tsirka, Stella E.; Scheel, Andreas H.; Bode, Daniel; Dobbelstein, Matthias; Brück, Wolfgang; Moll, Ute M.

doi:10.1038/cdd.2010.131

Cited by 102 publications

(144 citation statements)

References 41 publications

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“…Subsequently, however, these neurons develop abnormally, producing thinner, shorter and kinked neurites (Supplementary Figure S1c) as previously reported. 3,4 This iPSC system supports the notion that p73 blocks differentiation of progenitors independently of its pro-proliferative and anti-senescence action in maintaining the NSC niche. While this study reinforces p73 as a powerful factor in brain development, it also emphasizes that proper p73 expression should be monitored when developing neuronal differentiation protocols for iPSCs in the future for regenerative medicine.…”

supporting

confidence: 60%

“…1,3 In classic 3D-neurosphere assays from embryonic and newborn whole brains and isolated neurogenic niches, and in vivo tracking of adult neural stem cells (NSCs) in mice, p73 was unequivocally established as an essential regulator of NSC survival and renewal. [3][4][5] However, the question whether p73 is also required for the birth of NSCs from neuroectoderm in very early CNS development remained unanswered. The neurosphere assay is not capable of answering this question since it selects for already formed NSCs.…”

mentioning

confidence: 99%

“…To this end, we generated p73KO/Nestin-GFP and WT/ Nestin-GFP mice (Nestin-promoter, an NSC marker, drives GFP), 3 isolated mouse embryo fibroblasts from littermate embryos and reprogrammed them into iPSCs. 7 We used either three factors (3F; Klf4, Oct3/4 and Sox2) or two factors (2F; Klf4 and Oct3/4, to avoid possible effects from exogenous Sox2, an NSC regulator).…”

mentioning

confidence: 99%

“…Thus, these data clearly establish that p73 is not required for commitment to the neural fate and NSC formation, but is essential for NSC maintenance. [1][2][3][4][5][6] WT iPSCs in N2B27 medium continuously accumulated NSCs over 7 days or showed a slight decline after peaking at day 3-4. However, at day 7 the percentage of p73KO NSCs was reproducibly lower compared with WT (Supplementary Figure S1a).…”

mentioning

confidence: 99%

“…[1][2][3][4][5][6] Global p73 knockout (KO) exhibit defective embryonic and adult neurogenesis associated with cortical thinning, hydrocephalus and hippocampal dysgenesis. 1,3 In classic 3D-neurosphere assays from embryonic and newborn whole brains and isolated neurogenic niches, and in vivo tracking of adult neural stem cells (NSCs) in mice, p73 was unequivocally established as an essential regulator of NSC survival and renewal. [3][4][5] However, the question whether p73 is also required for the birth of NSCs from neuroectoderm in very early CNS development remained unanswered.…”

mentioning

confidence: 99%

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p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

2012

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confidence: 60%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

2012

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Cortical hypoplasia and ventriculomegaly of p73‐deficient mice: Developmental and adult analysis

Medina-Bolívar

González‐Arnay

Talos

et al. 2014

J of Comparative Neurology

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Trp73, a member of the p53 gene family, plays a crucial role in neural development. We describe two main phenotypic variants of p73 deficiency in the brain, a severe one characterized by massive apoptosis in the cortex leading to early postnatal death and a milder, non-/low-apoptosis one in which 50% of pups may reach adulthood using an intensive-care breeding protocol. Both variants display the core triad of p73 deficiency: cortical hypoplasia, hippocampal malformations, and ventriculomegaly. We studied the development of the neocortex in p73 KO mice from early embryonic life into advanced age (25 months). Already at E14.5, the incipient cortical plate of the p73 KO brains showed a reduced width. Examination of adult neocortex revealed a generalized, nonprogressive reduction by 10-20%. Area-specific architectonic landmarks and lamination were preserved in all cortical areas. The surviving adult animals had moderate ventricular distension, whereas pups of the early lethal phenotypic variant showed severe ventriculomegaly. Ependymal cells of wild-type ventricles strongly express p73 and are particularly vulnerable to p73 deficiency. Ependymal denudation by apoptosis and reduction of ependymal cilia were already evident in young mice, with complete absence of cilia in older animals. Loss of p73 function in the ependyma may thus be one determining factor for chronic hydrocephalus, which leads to atrophy of subcortical structures (striatum, septum, amygdala). p73 Is thus involved in a variety of CNS activities ranging from embryonic regulation of brain size to the control of cerebrospinal fluid homeostasis in the adult brain via maintenance of the ependyma.

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p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture

Gonzalez-Cano

Fuertes-Alvarez

Robledinos-Antón

et al. 2015

Developmental Neurobiology

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The adult subventricular zone (SVZ) is a highly organized microenvironment established during the first postnatal days when radial glia cells begin to transform into type B‐cells and ependymal cells, all of which will form regenerative units, pinwheels, along the lateral wall of the lateral ventricle. Here, we identify p73, a p53 homologue, as a critical factor controlling both cell‐type specification and structural organization of the developing mouse SVZ. We describe that p73 deficiency halts the transition of the radial glia into ependymal cells, leading to the emergence of immature cells with abnormal identities in the ventricle and resulting in loss of the ventricular integrity. p73‐deficient ependymal cells have noticeably impaired ciliogenesis and they fail to organize into pinwheels, disrupting SVZ niche structure and function. Therefore, p73 is essential for appropriate ependymal cell maturation and the establishment of the neurogenic niche architecture. Accordingly, lack of p73 results in impaired neurogenesis. Moreover, p73 is required for translational planar cell polarity establishment, since p73 deficiency results in profound defects in cilia organization in individual cells and in intercellular patch orientation. Thus, our data reveal a completely new function of p73, independent of p53, in the neurogenic architecture of the SVZ of rodent brain and in the establishment of ependymal planar cell polarity with important implications in neurogenesis. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 730–747, 2016

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p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis

Cited by 102 publications

References 41 publications

p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

Cortical hypoplasia and ventriculomegaly of p73‐deficient mice: Developmental and adult analysis

p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture

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