Neural tube development requires the cooperation of p53‐ and Gadd45a‐associated pathways

Abstract

BACKGROUND:Numerous genetically engineered mouse models for neural tube defects (NTDs) exist, and some of the implicated proteins are functionally related. For example, the growth arrest and DNA damageinducible protein Gadd45a and tumor suppressor p53 are functionally similar, and both are involved in neural tube development (Gadd45a-and Trp53-null embryos show low levels of exencephaly). To assess their roles in neural tube development, we generated double-null mice from Gadd45a-and Trp53-null mice, as well as from cyclin-dependent kinase inhibitor (Cdkn1a) (p21)-null and xeroderma pigmentosum group C (XPC)-null mice that do not show spontaneous exencephaly. METHODS: Gadd45a-, Trp53-, Cdkn1a-, and XPC-null mice were crossed to generate several double-null mouse models. Embryos (embryonic day [ED] 16 -18) from the single-and double-null crosses were scored for NTDs. RESULTS: Deletion of both Gadd45a and Trp53 in mice increased exencephaly frequencies compared to the deletion of either single gene (34.0% in Gadd45a/Trp53-null compared to 8.4% and 9.1% in the Gadd45a-and Trp53-null embryos, respectively). Furthermore, although deletion of another p53-regulated gene, Cdkn1a, is not associated with exencephaly, in conjunction with Gadd45a deletion, the exencephaly frequencies are increased (30.5% in the Gadd45a/Cdkn1a-null embryos) and are similar to those in the Gadd45a/Trp53-null embryos. Although XPC deletion increased exencephaly frequencies in Trp53-null embryos, XPC deletion did not increase the exencephaly frequencies in Gadd45a-null embryos. CONCLU-SIONS: The increased genetic liability to exencephaly in the Gadd45a/Trp53-and Gadd45a/Cdkn1a-null embryos may be related to the disruption of multiple cellular pathways associated with Gadd45a and p53. Birth Defects Research (Part A) 76:129 -132, 2006.

Sex difference in neural tube defects in p53‐null mice is caused by differences in the complement of X not Y genes

“…Of the 98 mice at postnatal day one (P1), 13 were homozygous Trp53 null (À/À), of which all were male (Table 1, p ¼ 0.0009, FET). The 100% lethality in females is higher than has been reported for Trp53 null mice in the other inbred or outbred strains (Armstrong et al, 1995;Sah et al, 1995;Embree-Ku and Boekelheide, 2002;Patterson et al, 2006), suggesting that the effects of the mutation are greater on the B6 background.…”

“…DNA repair-deficient mice lacking XRCC4 or DNA ligase IV show embryonic lethality and massive neuronal apoptosis that is rescued by Trp53 mutation Gao et al, 2000). The NTD phenotype of Trp53 mutant mice is synergistically exacerbated by mutations in DNA damage response genes Gadd45a, XPC (Patterson et al, 2006) or Msh2 (Cranston et al, 1997;Cranston and Fishel, 1999). Together with Trp53, these functions are involved in apoptosis, genomic instability, cell cycle control, and/ or DNA repair and their absence leads to an accumulation of mutations and genome rearrangements.…”

“…Importantly, the lack of p53 affects females predominantly, many of which die in utero or soon after birth. The sex difference and penetrance of the NTD effect in nullizygous Trp53 mice seem to be greater on inbred than on outbred strain backgrounds (Armstrong et al, 1995;Sah et al, 1995;Cranston and Fishel, 1999;Patterson et al, 2006), and is exacerbated by combining nullizygoisty for Trp53 with nullizygosity for the DNA mismatch repair gene Msh2 (Cranston et al, 1997;Cranston and Fishel, 1999), the nucleotide excision repair gene XPC or DNA damage response gene Gadd 45a (Patterson et al, 2006). The origins of the female bias in NTDs are not known.…”

Effect of maternal Tp53 gene G412C polymorphism on neural tube defects: A study from North India

“…[6] On the other hand, around 8-16% of p53-deficient female mice exhibited exencephaly,[15] and the levels of exencephaly increased in double knockouts for p53 and Gadd45a (growth arrest and DNA-damage-inducible protein alpha), which is a one of the downstream effectors induced by p53 to achieve G2-M arrest. [7] Pregnant p53 deficient mice are at higher risk of reduced blastocyst implantation;[16] however, development of neural tube or its defects, condition which is considered in the present study, arises only after the blastocyst implantation of an embryo.…”

“…Mouse model studies suggested suppression of p53 mediated apoptotic activity rescues NTDs,[4–6] but also, p53 deficient mice exhibit exencephaly. [7]…”