Leptin is detected in the sera, and leptin receptors are expressed in the cerebrum of mouse embryos, suggesting that leptin plays a role in cerebral development. Compared with the wild type, leptin-deficient (ob/ob) mice had fewer cells at embryonic day (E) 16 and E18 and had fewer 5-bromo-2'-deoxyuridine(+) cells at E14 and E16 in the neuroepithelium. Intracerebroventricular leptin injection in E14 ob/ob embryos increased the number of neuroepithelium cells at E16. In cultured neurosphere cells, leptin treatment increased Hes1 mRNA expression and maintained neural progenitors. Astrocyte differentiation was induced by low-dose (0.1 microg/ml) but not high-dose (1 microg/ml) leptin. High-dose leptin decreased Id mRNA and increased Ngn1 mRNA in neurosphere cells. The neuropeptide Y mRNA level in the cortical plate was lower in ob/ob than the wild type at E16 and E18. These results suggest that leptin maintains neural progenitors and is related to glial and neuronal development in embryos.

Type 1 diabetes, a multifactorial disease involving genetic and environmental factors, results from the destruction of pancreatic ␤-cells. The maternal environment has been suggested to be important in the development of diabetes. To assess the role of maternal factors in the development of insulitis and overt diabetes, we transplanted pre-implantation stage embryos of nonobese diabetic (NOD) mice, a model of type 1 diabetes, into the uterus of each recipient. Recipients were ICR and DBA/2J mice without diabetic genetic predisposition and NOD mice not exhibiting overt diabetes during the experiment; offspring were designated as NOD/ICR, NOD/DBA, and NOD/NOD, respectively; unmanipulated NOD offspring were also examined. NOD/ICR and NOD/ DBA offspring developed insulitis significantly earlier than NOD/NOD offspring. However, overt diabetes was significantly suppressed in NOD/ICR and NOD/DBA offspring in comparison with NOD/NOD offspring. Insulin autoantibodies (IAAs) were undetectable in ICR and DBA/2J surrogate mothers and in NOD/ICR and NOD/ DBA offspring at the onset of insulitis, suggesting that maternal factors other than transmitted IAAs induced the earlier onset. The present study indicates that altered maternal factors modify the immune response to islets, which in turn might affect the pathogenic course from insulitis to overt diabetes. Diabetes 54:2026 -2031, 2005 H uman type 1 diabetes is characterized by the establishment of autoimmune insulitis, which precedes ␤-cell destruction, culminating in hypoinsulinemia and hyperglycemia. Human type 1 diabetic patients spontaneously develop a diabetic syndrome that is controlled by both genetic and environmental factors (1,2). The environmental triggers of islet autoimmunity and type 1 diabetes are essentially unknown but are considered likely to operate early in life, possibly even in utero (3). Previous studies have linked the risk of type 1 diabetes to congenital rubella infection, but noncongenital infection does not appear to convey this risk, indicating the importance of pre-or perinatal events as triggers of islet autoimmunity (4 -6). It has been suggested that maternal environment and maternally transmitted insulin autoantibodies (IAAs) in particular modify the risk of the development of autoimmune diabetes in offspring (7); however, it was recently reported (8) that fetal exposure to IAAs did not increase the risk of diabetes development in nonobese diabetic (NOD) mice. The exact role of maternal environmental factors and their relationship in the initiation and modification of the pathogenesis of diabetes in each diabetic individual remain largely unknown. In our previous study (9), by transplanting NOD embryos into the uterus of a recipient ICR mouse, we analyzed genetic predisposition versus diabetic environment and the interaction between these two factors in NOD embryos as causes of congenital malformation.In the present study, using the same experimental strategy, the onset and incidence of insulitis and overt diabetes were examined in offspring ...

Although chromosomal segregation at meiosis I is the critical process for genetic reassortment and inheritance, little is known about molecules involved in this process in metazoa. Here we show by utilizing doublestranded RNA (dsRNA)-mediated genetic interference that novel protein kinases (Ce-CDS-1 and Ce-CDS-2) related to Cds1 (Chk2) play an essential role in meiotic recombination in Caenorhabditis elegans. Injection of dsRNA into adult animals resulted in the inhibition of meiotic crossing over and induced the loss of chiasmata at diakinesis in oocytes of F 1 animals. However, electron microscopic analysis revealed that synaptonemal complex formation in pachytene nuclei of the same progeny of injected animals appeared to be normal. Thus, Ce-CDS-1 and Ce-CDS-2 are the first example of Cds1-related kinases that are required for meiotic recombination in multicellular organisms.Protein kinases play crucial roles in the regulation of a wide variety of cellular functions. A novel family of protein kinases, bearing a phosphospecific protein-protein interaction motif, the forkhead-associated (FHA) domain (11), has been identified and shown to be involved in checkpoint regulation and DNA repair induced by DNA damage (16). Protein kinases belonging to this family include Saccharomyces cerevisiae Rad53, Dun1, and Mek1p (MRE4), Schizosaccharomyces pombe Cds1 and Mek1, Drosophila melanogaster Dmnk, and mammalian Chk2 (5,7,19,20,23,26,36,43). It has been reported that the yeast Rad53, Cds1, and Dun1 protein kinases are required for the S-phase checkpoint and for the activation of the DNA repair machinery upon DNA damage, although Dun1 is involved only in the latter process (2,12,23,25,36,42,43). In contrast, S. cerevisiae Mek1p is involved in the regulation of meiotic recombination (19).It has recently been reported that, in response to DNA damage and DNA replicational stress, Chk2 (mammalian Cds1) is activated and phosphorylates Cdc25C, thereby inactivating Cdc25 phosphatase activity and preventing entry of cells into mitosis (5,7,8,20,39). More recently, Chk2 has been shown to stabilize p53 by phosphorylating p53 on serine 20, which interferes with Mdm2 binding (9,14,35). In contrast, D. melanogaster Dmnk, which is most closely related to Chk2, is highly expressed in ovaries and in germ cell nuclei during early embryogenesis, suggesting its possible function(s) in char- acteristic features of germ cells such as meiosis and/or germline establishment (26).Caenorhabditis elegans is an excellent model organism in which to study meiosis, the cell cycle, and development. With the determination of the entire genomic sequence of C. elegans, this multicellular organism further provides a unique opportunity to study the role of this entire gene family during development. Specific and functional disruption of gene expression by utilizing double-stranded RNA (dsRNA)-mediated genetic interference (RNAi) enables us to address the biological consequence of reduction or elimination of the activity of a particular gene (4,13,34). To exam...

Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. In the present study, to investigate the effect of maternal or post-weaning offspring's nutrition, in particular the essential fatty acid ratio (n-6/n-3) on the development of type 1 diabetes, we prepared two kinds of chows with n-6/n-3 ratios of 3.0 (L) and 14.5 (H), and provided them to mothers of non-obese diabetic (NOD) mice during gestation and lactation and to the offspring after weaning. The n-6/n-3 ratios in breast milk and erythrocyte membrane of NOD offspring became nearly the same with that of the maternal diet at 2 weeks after birth. In the L chow-fed offspring from L chow-fed mother (LLL), levels of insulitis were higher than those in the H chow-fed offspring from H chow-fed mother (HHH) at 4 weeks of age, while the levels in the LLL offspring became lower than those in the HHH after 6 weeks. Early insulin autoantibody expressions were found from 2 to 6 weeks in the HHH offspring, but not in the LLL. The LLL offspring exhibited strong suppression of overt diabetes development in regard to the onset and accumulated incidence of diabetes compared to the HHH. The study with combined L and H chows during gestation, lactation in mother and in post-weaning offspring revealed that only the LLH chow significantly suppressed the development of diabetes with similar kinetics to LLL chow, although the other combinations may delay the onset of diabetes. The present findings suggest that n-6/n-3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in NOD mice.