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The generation of viable sperm proceeds through a series of coordinated steps, including germ cell self-renewal, meiotic recombination, and terminal differentiation into functional spermatozoa. The p53 family of transcription factors, including p53, p63, and p73, are critical for many physiological processes, including female fertility, but little is known about their functions in spermatogenesis. Here, we report that deficiency of the TAp73 isoform, but not p53 or ΔNp73, results in male infertility because of severe impairment of spermatogenesis. Mice lacking TAp73 exhibited increased DNA damage and cell death in spermatogonia, disorganized apical ectoplasmic specialization, malformed spermatids, and marked hyperspermia. We demonstrated that TAp73 regulates the mRNA levels of crucial genes involved in germ stem/progenitor cells (CDKN2B), spermatid maturation/spermiogenesis (metalloproteinase and serine proteinase inhibitors), and steroidogenesis (CYP21A2 and progesterone receptor). These alterations of testicular histology and gene expression patterns were specific to TAp73 null mice and not features of mice lacking p53. Our work provides previously unidentified in vivo evidence that TAp73 has a unique role in spermatogenesis that ensures the maintenance of mitotic cells and normal spermiogenesis. These results may have implications for the diagnosis and management of human male infertility. published

Significance p73 is a tumor suppressor protein that also plays a central role in brain development. But how p73 modulates neurite outgrowth and neurite arborization is not clear. Neurotrophins are small molecules, which send signals between cells. Neurotrophins can induce cells to either apoptosis or survival. We show that TAp73 is a transcriptional activator of the p75 neurotrophin receptor (p75 NTR ). TAp73 knockout mice have reduced levels of p75 NTR and show peripheral nerve defect, including reduced myelin thickness and thermal sensitivity. p75 NTR is expressed most strongly in the peripheral nerve, where it is important for nerve development. Relatively limited information exists on p75 NTR gene regulation; by linking the p53/p73 gene family to p75 NTR transcription, we introduce possibly controversial mechanisms of regulation.