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.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/ETD-TAMU-3251 |
| Date | 15 May 2009 |
| Creators | Hosako, Hiromi |
| Contributors | Mirkes, Philip E, Safe, Stephen H |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | electronic, application/pdf, born digital |
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