The role of p53 in normal development and teratogen-induced apoptosis and birth defects in mouse embryos

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Title: The role of p53 in normal development and teratogen-induced apoptosis and birth defects in mouse embryos
Author: Hosako, Hiromi
Abstract: In the studies described in this dissertation , we investigated the roles of p53 in normal development , teratogen -induced apoptosis , and birth defects . In the first study , the activation of p53 and its target genes , p21 , NOXA , and PUMA , were examined during neural tube closure in mouse embryos exposed to hyperthermia (HS ) or 4 - peroxycyclophosphamide (4CP ) , teratogens known to induce neural tube defects (NTDs ) . In the second study , using p53 -deficient mice , we examined the expression of mRNAs and microRNAs (miRNAs ) during neural tube closure . In the third study , the incidence of NTDs was investigated in p53 - and p21 -deficient mouse embryos exposed to HS . Finally , we examined the induction of apoptosis in p53 -deficient mouse embryos exposed to HS . HS and 4CP induced the activation of p53 by phosphorylation and accumulation of the protein , leading to an increase in p21 proteins and mRNAs . Although HS and 4CP also induced the expression of Noxa and Puma mRNAs , no significant increases in NOXA and PUMA proteins were observed , suggesting a possible role of transcriptionindependent apoptosis . In the second study , we showed that the expression of 388 genes and 5 miRNAs were significantly altered in p53 - / - compared to p53 + /+ embryos . Finally , we showed that 10 % of p53 - / - pups exhibit exencephaly , spina bifida , and /or preaxial polydactyly , whereas no malformations were observed among p21 - / - offspring in the absence of HS . HS resulted in an increased incidence of exencephaly in both p53 and p21 null mice indicating that these two proteins act as teratogen suppressors . Our preliminary data additionally showed that a decreased level of apoptosis was observed in HS -treated embryos lacking a p53 allele , suggesting that too little apoptosis may be causally linked to NTDs observed in embryos exposed to HS . Taken together , these studies suggest that precise control of apoptosis and cell cycle arrest pathways are critical for neural tube development and the prevention of teratogen -induced NTDs .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -3251
Date: 2009-05-15

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The role of p53 in normal development and teratogen-induced apoptosis and birth defects in mouse embryos. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -3251 .

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