Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality.

Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1(-/-) mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1(-/-) blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1(+/-) mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1(cko/-)) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1(cko/+)-Ndel1(+/-) mice or Lis1(+/-)-Ndel1(+/-) mice displayed more severe neuronal migration defects than Lis1(cko/+)-Ndel1(+/)(+) mice or Lis1(+/-)-Ndel1(+/+) mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of beta-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration.

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality.

The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N'-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.

Heteropagus conjoined twins due to fusion of two embryos: report and review.

We report on a case of conjoined twinning (CT) consistent with fusion of two embryos followed by resorption of the cranial half of one of them, resulting in a normal male baby with the lower half of a male parasitic twin fused to his chest. Fluorescent in situ hybridization (FISH) studies suggested that the parasitic twin was male, and DNA typing studies demonstrated dizygosity. Although incomplete fission is the usual explanation for conjoined twins, the unusual perpendicular orientation of the parasite to the autosite supports a mechanism observed in mares in which early fusion of two embryos is followed by resorption due to compromised embryonic polarity.

[Parthenogenesis in mammals]. / Partenogenez mlekopitaiushchikh.

A review of studies dealing with spontaneous and induced parthenogenesis in mammals. The main methods of artificial egg activation, ways of their development and causes of mortality of the parthenogenetic mouse embryos are considered. The possibilities of using parthenogenesis for solving urgent problems of mammalian developmental biology are estimated and prospects of further studies in this field are outlined.

[Effect of monosomy of the autosomes on the preimplantation stages of embryogenesis in laboratory mice]. / Vliianie monosomii nekotorykh autosom na doimplantatsionnye stadii émbriogeneza laboratornykh myshei.

The effects of monosomy for the autosomes 1, 2, 3, 5, 6, 16 and 19 were studied in mice with single or double Robertsonian translocations. The monosomy for different autosomes affects the preimplantation development of the mouse embryos in different ways. The monosomy for the autosomes 1, 3, 6, 16 or 19 does not affect cleavage, compactization or blastulation and is, in some cases, even compatible with the implantation. The most these embryos are eliminated at the blastocyst stage (monosomy for the autosomes 3, 6 or 19) or, sometimes, at the postimplantation stages (1 or 16). The monosomy for the autosomes 2 or 5 is realized during cleavage causing the developmental delay, pathological changes in the nuclei of blastomeres and elimination at the morula stage. The results obtained suggest differential activity of chromosomes at the preimplantation stages of embryogenesis. Possible reasons for the early death of the embryos with particular types of monosomy are discussed. A hypothesis of mutual activation of the homologous autosomes at the early developmental stages is put forward. According to this hypothesis, the loci of a single unpaired autosome, especially of paternal origin, remain inactive during the early embryogenesis.

[Embryo survival rate of BALB and C57BL line mice in reciprocal transplantations at early stages of development]. / Vyzhivaemost' émbrionov myshei linii BALB i C57BL pri ikh retsiproknykh peresadkakh na rannikh stadiiakh razvitiia.

Survival rate and weight were studied for the BALB/c and C57Bl/6J mice embryos developed from transplanted 2- and 3-day-old blastocysts. The greatest number of implantations was observed when 3-day-old blastocysts were transplanted to recipient females with two-day pregnancy. The number of implantations and successfully developing transplanted embryos was increased in recipient female with a higher number of corpora lutea.