TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor

Abstract

Total and N-terminal isoform selective p73 knockout mice show a variety of central nervous system defects. Here we show that TAp73 is a transcriptional activator of p75 neurotrophin receptor (p75 NTR ) and that p75 NTR mRNA and protein levels are strongly reduced in the central and peripheral nervous systems of p73 knockout mice. In parallel, primary cortical neurons from p73 knockout mice showed a reduction in neurite outgrowth and in nerve growth factor-mediated neuronal differentiation, together with reduced miniature excitatory postsynaptic current frequencies and behavioral defects. p73 null mice also have impairments in the peripheral nervous system with reduced thermal sensitivity, axon number, and myelin thickness. At least some of these morphological and functional impairments in p73 null cells can be rescued by p75 NTR re-expression. Together, these data demonstrate that loss of p75 NTR contributes to the neurological phenotype of p73 knockout mice.73 is a transcription factor belonging to the p53 family, whose members share similarities in sequence and function (1-4). p73 can be transcribed from two different promoters: transcription from the upstream P1 promoter generates TAp73 isoforms containing a transactivation (TA) domain, and transcription from the P2 promoter generates truncated proteins that lack the TA domain and are known as ΔNp73. The C-terminal region of p73 is expressed, at least at the mRNA level, as a number of alternatively spliced TAp73 and ΔNp73 C-terminal isoforms (α, β, γ, ζ, δ, e, η), although it remains unclear whether all of these are also represented at the protein level (5, 6).The p75 neurotrophin receptor (p75 NTR ) is a member of the death receptor family, which can also be expressed in a variety of isoforms and functions as a low-affinity receptor for neurotrophins (7,8). It is abundantly expressed on neurons and glia in the developing nervous system (as well as on some other cell types such as B lymphocytes and natural killer cells), although it is much less abundant in adult brain. The effects of ligand binding to p75 NTR depend on p75 NTR 's interaction with other coreceptors. Thus, interaction with tropomyosin-related kinase A (TrkA) results in high-affinity binding of neurotrophins such as nerve growth factor (NGF) and cell survival. In contrast, neurotrophin interaction with the p75 NTR /sortilin complex leads to apoptosis, whereas p75 NTR can also form part of the Nogo receptor complex, which is activated by myelin proteins to inhibit axonal growth (9). Deletion of p75 NTR results in a profound loss of sensory but not motor neurons in dorsal root ganglia, with an increase in basal forebrain cholinergic neurons, confirming that p75 NTR can mediate both survival and apoptotic effects. The defect in sensory innervation arises because the peripheral axons are stunted and show reduced arborization (10, 11). In the central nervous system, p75 NTR -deficient mice also show significantly reduced hippocampal neurogenesis, with a smaller granular cell layer and dentate gyrus,...

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…However, we cannot rule out that other transcription factors known to regulate p75 NTR expression might also contribute to p75 NTR deregulation. For instance, it was recently shown that p75 NTR is a direct transcriptional target of the transcriptional activator p73 (Tap73) (71), which has also been demonstrated to be hyperactive in HD mouse models and to play a relevant role in HD pathology (72). Interestingly, hippocampal p75…”

“…NTR and Tap73 expression is increased in AD (73,74), suggesting that the p73/p75 NTR axis may also play an important role in the pathology of neurodegenerative diseases (71).…”

How Does p73 Cause Neuronal Defects?

“…The p73−/− mice also have impaired reflex and neuromuscular function and sensorimotor coordination and increased anxiety. Many of these behavioral abnormalities observed in the p73−/− mice were also found in the TAp73−/− mice [36]. Hippocampal dysfunction is specifically associated with a reduction in burrowing and open field performance [53,54], and the TAp73−/− mice also exhibit a reduction in burrowing and in speed and rearing time in open field tests.…”

“…Accordingly, over 70 % of the TAp73 selective knockout mice (TAp73−/−) show an increased susceptibility to both spontaneous and induced carcinogenesis [34]. In addition, TAp73−/− mice are infertile and exhibit hippocampal dysgenesis, indicating a role for the TAp73 isoform in the regulation of reproduction and in neuronal development [35][36][37][38].…”

TAp73 transcriptionally represses BNIP3 expression

“…In fact, TAp73 is necessary for neuronal differentiation and maintenance of neuronal stem cells. [51][52][53][54] Hypoxia inducible factors (HIFs) mediate the physiological response to hypoxia 55 regulating processes, such as angiogenesis, [56][57][58] proliferation [59][60][61][62][63][64][65][66][67][68] and metabolism. 64,[69][70][71][72][73] The wide transcriptional reprogramming operated by HIF-1, includes the direct transcriptional induction of the Bcl-2 Nineteen kilodalton Interacting Protein (BNIP3).…”