p73: A Multifunctional Protein in Neurobiology

Abstract

p73, a transcription factor of the p53 family, plays a key role in many biological processes including neuronal development. Indeed, mice deficient for both TAp73 and ΔNp73 isoforms display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus. TAp73 expression increases in parallel with neuronal differentiation and its ectopic expression induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines and neural stem cells, suggesting that it has a pro-differentiation role. In contrast, ΔNp73 shows a survival function in mature cortical neurons as selective ΔNp73 null mice have reduced cortical thickness. Recent evidence has also suggested that p73 isoforms are deregulated in neurodegenerative pathologies such as Alzheimer’s disease, with abnormal tau phosphorylation. Thus, in addition to its increasingly accepted contribution to tumorigenesis, the p73 subfamily also plays a role in neuronal development and neurodegeneration.

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

“…[11][12][13][14][15] It is involved in several biological processes, such as cell death, [16][17][18][19] differentiation, [20][21][22] neuronal stem cell maintenance, [23][24][25][26] the amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53.…”

Characterization of Critical Domains within the Tumor Suppressor CASZ1 Required for Transcriptional Regulation and Growth Suppression

“…As in other cancers, transcription factors involved in development play a key role in the transformation of normal progenitors into malignant neuroblastoma (3,8,10,12,17,27). In humans, the transcription factor CASZ1 (also known as Castor or Cas), which localizes to chromosome 1p36, has been shown to be frequently deleted in neuroblastoma as well as other types of cancers, such as oligodendroglioma and breast cancer (1).…”

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

“…[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.…”

“…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).…”