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p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours

Abstract

p73 (ref. 1) has high homology with the tumour suppressor p53 (refs 2,3,4), as well as with p63, a gene implicated in the maintenance of epithelial stem cells5,6,7. Despite the localization of the p73 gene to chromosome 1p36.3, a region of frequent aberration in a wide range of human cancers1, and the ability of p73 to transactivate p53 target genes1, it is unclear whether p73 functions as a tumour suppressor. Here we show that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways. In contrast to p53-deficient mice, however, those lacking p73 show no increased susceptibility to spontaneous tumorigenesis. We report the mechanistic basis of the hippocampal dysgenesis and the loss of pheromone responses, and show that new, potentially dominant-negative, p73 variants are the predominant expression products of this gene in developing and adult tissues. Our data suggest that there is a marked divergence in the physiological functions of the p53 family members, and reveal unique roles for p73 in neurogenesis, sensory pathways and homeostatic control.

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Figure 1: Targeted disruption of the murine p73 gene.
Figure 2: Somatic growth defects and mortality in p73-/- pups.
Figure 3: Hippocampal dysgenesis and reelin expression.
Figure 4: Reelin expression in wild-type and p73-/- P3 mice.
Figure 5: a, Left, autoradiograph of wild-type vomeronasal organ showing p73 transcript expression in the neurosensory epithelim (ne).

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Acknowledgements

We would like to thank F. Borriello, H. Green, C. Westphal, P. Ferrara, T. Rapoport and L. Buck for helpful discussions; L. Du for blastocyst injections; A. Goffinet for the reelin antibody; H. Liu for the mouse genomic library; and J. Williams for histology preparation. This work was supported by the American Cancer Society and the Council for Tobacco Research (F.M.), and the NIH (R.B., A.S., P.D. and F.M.).

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Correspondence to Frank McKeon or Daniel Caput.

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Yang, A., Walker, N., Bronson, R. et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99–103 (2000). https://doi.org/10.1038/35003607

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