200 j Journal of Molecular Cell Biology (2019), 11(3), 200–211 doi:10.1093/jmcb/mjy087 Published online January 8, 2019 Review The role of p53 in developmental syndromes Margot E. Bowen1 and Laura D. Attardi1,2,* 1 Division of Radiation and Cancer Biology in the Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA * Correspondence to: Laura D. Attardi, E-mail: [email protected] Edited by Chandra S. Verma While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer, growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic syndromes. The inherited or de novo mutations that cause these syndromes affect diverse cellular processes, such as ribosome biogenesis, DNA repair, and centriole duplication, and analysis of human patient samples and mouse models demonstrates that disrupting these cellular processes can activate the p53 pathway. Importantly, many of the developmental defects in mouse models of these syndromes can be rescued by loss of p53, indicating that inappropriate p53 activation directly contributes to their pathogenesis. A role for p53 in driving developmental defects is further sup- ported by the observation that mouse strains with broad p53 hyperactivation, due to mutations affecting p53 pathway components, dis- play a host of tissue-specific developmental defects, including hematopoietic, neuronal, craniofacial, cardiovascular, and pigmentation defects. Furthermore, germline activating mutations in TP53 were recently identified in two human patients exhibiting bone marrow fail- ure and other developmental defects. Studies in mice suggest that p53 drives developmental defects by inducing apoptosis, restraining proliferation, or modulating other developmental programs in a cell type-dependent manner. Here, we review the growing body of evi- dence from mouse models that implicates p53 as a driver of tissue-specific developmental defects in diverse genetic syndromes. Keywords: p53, Mdm2, development, embryo, congenital defect, syndrome, genetic disorder Introduction ∼20 53 The p53 tumor suppressor protein is a transcription factor development of certain tissues, with % of female p -defi- that acts as a central hub in the cellular response to stress. cient mouse embryos exhibiting neonatal lethality due to the 53 While normally maintained at low levels in the cell, p53 neural tube defect exencephaly, and a subset of p -deficient becomes stabilized and activated in response to a variety of mice displaying growth retardation or subtle developmental cellular stresses, such as DNA damage and hyperproliferative defects affecting the palate, eyes, teeth, lungs, or kidneys 1995 1995 1997 signals, and induces genes involved in numerous cellular pro- (Armstrong et al., ; Sah et al., ; Kaufman et al., ; 2002 2009 2011 cesses, including apoptosis, cell cycle arrest, DNA repair, and Baatout et al., ; Saifudeen et al., ; Rinon et al., ; 2015 metabolism (Bieging et al., 2014). Given p53’s central role in Tateossian et al., ). On the other hand, inappropriate acti- 53 regulating these diverse cellular responses, either loss of p53 vation of p can trigger cellular responses such as excessive or inappropriate activation of p53 can have pathological conse- apoptosis and therefore can also profoundly disrupt tissue 2014 quences. On the one hand, p53 is a potent tumor suppressor development and homeostasis (Van Nostrand et al., ; Wu 2018 53 and loss of p53 allows cells to expand under adverse condi- and Prives, ). In this regard, increased p activity is tions, thereby facilitating the growth of malignant cells (Kaiser thought to contribute to the developmental defects and prema- and Attardi, 2018). Loss of p53 can also perturb the ture aging phenotypes in numerous genetic syndromes and to the excessive neuronal cell death in various neurodegenerative disorders (Van Nostrand and Attardi, 2014; Lessel et al., 2017; Received July 20, 2018. Revised November 22, 2018. Accepted January 6, 2019. Szybin´ska and Les´niak, 2017; Wu and Prives, 2018). Thus, a © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. broad spectrum of human diseases arises as a consequence of This is an Open Access article distributed under the terms of the Creative either increased or decreased p53 activity. In this review, we Commons Attribution Non-Commercial License (http://creativecommons.org/ will discuss the growing body of evidence implicating p53 licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For com- hyperactivation as a driver of developmental defects in a wide mercial re-use, please contact [email protected]. range of genetic syndromes. The role of p53 in developmental syndromes j 201 Broadly activating p53 during mouse embryogenesis promotes detected in certain cell compartments in these mouse strains, such tissue-specific developmental defects as the embryonic neuroepithelium and the neonatal bone marrow Analyses from a variety of mouse strains demonstrate that and cerebellum (Liu et al., 2007; Terzian et al., 2007; Van Nostrand inappropriately activating p53 during embryonic and early post- et al., 2014). In addition, alterations in specific developmental pro- natal development triggers a host of developmental defects. In grams have been reported. In particular, mice with increased p53 these mouse strains, p53 hyperactivation has been achieved activity display impaired endothelial-to-mesenchymal transition of through mutations in Trp53, the gene encoding p53,ormutations endocardial cells during heart morphogenesis (Zhang et al., 2012a). in Mdm2 or Mdm4, which encode the two main negative regula- Furthermore, their keratinocytes display increased expression of tors of p53 that act cooperatively to inhibit the transactivation the p53 target gene Kitl, which encodes a melanocyte-stimulating domains of p53 andtotargetp53 for ubiquitin-mediated degrad- growth factor that promotes skin hyperpigmentation (McGowan ation (Figure 1AandB)(Perry, 2010). These mouse strains display et al., 2008; Pant et al., 2016; Chang et al., 2017). These studies a range of developmental phenotypes, the most striking of which suggest that inappropriate p53 activation drives developmental occur in Mdm2- and Mdm4-null mice, which exhibit p53-dependent defects by triggering apoptosis, restraining proliferation, or modu- lethalitybyembryonicday5.5 (E5.5)andE8.5, respectively lating other developmental programs in a cell type-dependent man- (Figure 1BandC)(Jones et al., 1995; Montes de Oca Luna et al., ner during embryonic and postnatal development. The molecular 1995; Parant et al., 2001; Chavez-Reyes et al., 2003; Moyer et al., basis for this cell type-specificity is not well understood. In other 2017). Mouse strains with milder levels of p53 hyperactivation— contexts, such as in cancer cell lines, multiple mechanisms have due to only partial loss of Mdm2 or Mdm4,orduetotheexpres- been proposed to explain why p53 activation elicits different sion of mutant p53 proteins with modestly enhanced stability or responses in different cell types. These mechanisms include cell activity—survive beyond early embryogenesis and display defects type-specific p53 post-translational modifications or expression only at later developmental stages (Figure 1BandC).Theageof of co-factors that influence which target genes p53 induces in a lethality of these mice varies based on the exact degree of p53 given cell type, as well as cell type-specific differences in the hyperactivation, with some mouse strains dying at late embryonic basal expression levels of factors required for the execution of or early postnatal stages and displaying notable developmental downstream cellular responses, such as factors involved in the defects, and other mouse strains surviving into adulthood with no apoptotic pathway (Kruiswijk et al., 2015). Determining which of overt developmental defects but instead displaying premature these mechanisms accounts for the cell type-specific responses aging phenotypes or exhibiting enhanced tumor resistance (Garcı´a- elicited by p53 activation in embryonic and neonatal cells is an Cao et al., 2002; Tyner et al., 2002; Alt, 2003; Mendrysa et al., intriguing area for future research. 2003; Maier, 2004; Johnson et al., 2005; Mendrysa, 2006; Liu et al., 2010, 2007; Terzian et al., 2007, 2011; Wang et al., 2016, TP53 and MDM2 mutations can cause developmental defects 2011b; Hamard et al., 2013; Simeonova et al., 2013; Van Nostrand and premature aging phenotypes in humans et al., 2014; Pant et al., 2016; Mello et al., 2017). Interestingly, the While the analysis of various mouse strains carrying muta- developmental defects associated with these mouse strains are tions in Trp53 or Mdm2 clearly indicates that inappropriate p53 highly tissue-selective and include craniofacial, cardiovascular, and activation can cause developmental defects and premature neural tube defects, which manifest at embryonic stages, and hem- aging phenotypes in mice (Figure 1C), recent reports indicate atopoietic, pigmentation, and cerebellar defects, which manifest at that TP53 and MDM2 mutations can cause similar phenotypes early postnatal stages (Figure 1C). For example, Trp5325,26,53,54/+ in humans. Indeed, germline TP53