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.

Fig. 1

p73 gene structure. a Genomic organisation of p73 and representation of different splicing variants that give rise to the isoforms of p73. The P1 promoter generates the TA isoforms, while the P2 promoter produces the ΔN isoforms. b Schematic representation of the domains encoded by the different isoforms of p73. On top, there are indicated the aminoacids included in each domain. TA transactivation domain, DBD DNA-binding domain, OD oligomerization domain, SAM SAM domain, TID transactivation inhibitory domain

Fig. 2

Reduction of the putative stem cell in the dentate gyrus from p73^−/− mice. The dentate gyrus from day 7 after birth (P7) of normal (p73^+/+) and knockout (p73^−/−) mice was stained with antibodies to glial fibrillary acidic protein (GFAP) and nestin. Arrows indicate double-positive cells. Knockout mice show nearly half of GFAP/Nestin cells, indicating a very reduced stemness potential in these mice. GL granular cell layer, ML molecular cell layer, Hil hilus. Scale bars 50 μm

Fig. 3

Hippocampal neuron morphology is altered in the dentate gyrus of knockout (p73^−/−) mice. Golgi staining of dentate gyrus from normal (p73^+/+) and p73^−/− mice (age=18 days after birth). Knockout mice show reduced branching and connectivity of neurons. A representative photomicrograph is shown. Scale bars 100 μm (top panel) and 50 μm (low panel)

Fig. 4

Role of p73 in neurogenesis. Functional neurons are generated from neural stem cells and then after maturation, integrated in neuronal circuits. TAp73 is essential for neuronal differentiation and maintenance of neural stem cells. ΔNp73 plays a major role both as a survival mechanism as well as yet unknown pathways. Question marks indicate that molecular mechanism has not been fully investigated yet