The role of p53 in developmental syndromes

Abstract

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 supported by the observation that mouse strains with broad p53 hyperactivation, due to mutations affecting p53 pathway components, display 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 failure 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 evidence from mouse models that implicates p53 as a driver of tissue-specific developmental defects in diverse genetic syndromes.

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

“…Additional analysis of individual genes revealed that p53 signaling is increased in the XLID cells. These findings support the hypothesis that p53 activation might be a unique link between different genetic developmental disorders (13). Having established that the common feature of HUWE1-related XLIDs is deregulation of p53 pathway, we next focused on JMS, one of the most severe forms of XLID.…”

“…Only very few of the JMS organoids that did develop had decreased size, which is in line with the microcephaly observed in JMS patients (4), and were characterized by reduced cellularity and lack of the laminar patterning, features reported previously in the mouse Huwe1 mouse models (9,10). Interestingly, the observation that elevated p53 activity accompanies neurodevelopmental impairments in JMS is supported by 11 recent studies showing that patients with germline TP53 mutations present with microcephaly (27), as well as that microcephaly and neurodevelopmental defects in several human neurodevelopmental disorders are p53-dependent (13). This supports the idea that deregulation of p53 activity could have central role in the onset of various neurological conditions.…”

“…Transcription factor p53 controls expression of genes involved in cell 4 cycle, apoptosis and differentiation. While p53 has been extensively studied as tumor suppressor whose loss promotes cancer, several lines of evidence suggested that altered p53 activity contributes to the developmental defects in different human genetic syndromes (13).…”

The p53-p21 axis plays a central role in lymphatic homeostasis and disease

“…These mice exhibit radiosensitivity, decreased in-vitro transformation potential, and reduced in vivo tumorigenesis 9,10 . Several studies also revealed a role for p53 overexpression in developmental disorders 11,12 . For example, the ribosomopathy model with reduced expression of ribosomal protein Rpl27a, displays endogenously elevated p53 and phenocopies mouse models of high p53 13 .…”

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

“…The many biological functions and cellular processes regulated by p53 are also reflected by developmental syndromes that result from inappropriate p53 hyperactivation during embryogenesis, triggering apoptosis or restraining proliferation of certain cell types 5 . For other p53-controlled processes, like EMT and cellular differentiation, the etiology of these syndromes is currently unknown 5,6 . Many of these so-called p53-associated syndromes have been modeled in mice via introduction of mutations that affect various cellular processes converging on p53 activation.…”