Patterson Andrew D, Hildesheim Jeffrey, Fornace Albert J, Hollander M Christine
National Institutes of Health-George Washington University Graduate Partnerships Program in Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
Birth Defects Res A Clin Mol Teratol. 2006 Feb;76(2):129-32. doi: 10.1002/bdra.20217.
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 damage-inducible 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.
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.
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.
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.
存在众多用于研究神经管缺陷（NTDs）的基因工程小鼠模型，其中一些涉及的蛋白质在功能上相关。例如，生长停滞和DNA损伤诱导蛋白Gadd45a与肿瘤抑制因子p53在功能上相似，且二者均参与神经管发育（Gadd45a基因敲除和Trp53基因敲除的胚胎显示出较低水平的无脑畸形）。为评估它们在神经管发育中的作用，我们从Gadd45a基因敲除和Trp53基因敲除的小鼠，以及从细胞周期蛋白依赖性激酶抑制剂（Cdkn1a）（p21）基因敲除和着色性干皮病C组（XPC）基因敲除的小鼠（这些小鼠不表现出自发性无脑畸形）中培育出双基因敲除小鼠。
将Gadd45a、Trp53、Cdkn1a和XPC基因敲除的小鼠进行杂交，以生成几种双基因敲除小鼠模型。对单基因敲除和双基因敲除杂交后代的胚胎（胚胎期[ED]16 - 18）进行神经管缺陷评分。
与单个基因敲除相比，小鼠中Gadd45a和Trp53基因均缺失时无脑畸形频率增加（Gadd45a/Trp53基因双敲除胚胎中为34.0%，而Gadd45a基因敲除和Trp53基因敲除胚胎中分别为8.4%和9.1%）。此外，尽管另一个p53调控基因Cdkn1a的缺失与无脑畸形无关，但与Gadd45a基因缺失一起时，无脑畸形频率增加（Gadd45a/Cdkn1a基因双敲除胚胎中为30.5%），且与Gadd45a/Trp53基因双敲除胚胎中的频率相似。虽然XPC基因缺失会增加Trp53基因敲除胚胎中的无脑畸形频率，但XPC基因缺失不会增加Gadd45a基因敲除胚胎中的无脑畸形频率。
Gadd45a/Trp53基因双敲除和Gadd45a/Cdkn1a基因双敲除胚胎中无脑畸形遗传易感性增加可能与Gadd45a和p53相关的多个细胞通路的破坏有关。
