A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice.

Abstract

To directly assess c-myc function in cellular proliferation, differentiation, and embryogenesis, we have used homologous recombination in embryonic stem cells to generate both heterozygous and homozygous c-myc mutant ES cell lines. The mutation is a null allele at the protein level. Mouse chimeras from seven heterozygous cell lines transmitted the mutant allele to their offspring. The analysis of embryos from two clones has shown that the mutation is lethal in homozygotes between 9.5 and 10.5 days of gestation. The embryos are generally smaller and retarded in development compared with their littermates. Pathologic abnormalities include the heart, pericardium, neural tube, and delay or failure in turning of the embryo. Heterozygous females have reduced fertility owing to embryonic resorption before 9.5 days of gestation in 14% of implanted embryos, c-Myc protein is necessary for embryonic survival beyond 10.5 days of gestation; however, it appears to be dispensable for cell division both in ES cell lines and in the the embryo before that time.

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

“…[21][22][23] Furthermore, addition of interleukin 4 to anti-CD40-activated B lymphocytes renders these cells more resistant to CD95-induced cell death. 24 Inactivation of c-myc gene in the germ line results in embryonic lethality at day 9.5. 24 We have previously reported the generation of a conditional in vivo model to study c-myc function in B lymphocytes.…”

“…24 Inactivation of c-myc gene in the germ line results in embryonic lethality at day 9.5. 24 We have previously reported the generation of a conditional in vivo model to study c-myc function in B lymphocytes. 25 Now, we have bred c-myc fl/fl ; CD19 cre with a ROSA26-EGFP 'reporter' mouse, in order to circumvent the problems associated with incomplete deletion of the c-myc gene, [25][26][27] and extended our studies to characterize the role of c-myc in programmed cell death in primary B lymphocytes.…”

Apoptosis-prone phenotype of human colon carcinoma cells with a high level amplification of the c-myc gene

“…In normal cells, c-myc expression is tightly controlled by mitogenic stimuli and appears to be necessary, and in some instances su cient, to promote cell proliferation (reviewed by Evan and Littlewood, 1993), as well as to suppress di erentiation (reviewed by Ho man and Liebermann, 1994). The observation that disruption of c-Myc function by gene targeting is associated with severe growth impairment and a subsequent lethal phenotype (Davis et al, 1993) con®rms the essential role of this proto-oncogene in the regulation of cell proliferation. However, under some circumstances, cMyc can also act as a potent inducer of apoptosis.…”

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

“…Targeted mutations of the c-Myc and N-Myc genes have revealed their crucial roles in development. A c-Myc null mutation resulted in lethality of homozygous mice between days 9.5 and 10.5 of gestation (Davis et al, 1993). The c-Myc 7/7 embryos were smaller and exhibited retarded development relative to wild-type embryos indicating, that while able to proliferate initially, they were unable to sustain the growth necessary for later development.…”