Critical to our understanding of the developmental potential of stem cells and subsequent control of their differentiation in vitro and in vivo is a thorough understanding of the genes that control stem cell fate. Here, we report that Foxd3, a member of the forkhead family of transcriptional regulators, is required for maintenance of embryonic cells of the early mouse embryo. Foxd3−/− embryos die after implantation at approximately 6.5 days postcoitum with a loss of epiblast cells, expansion of proximal extraembryonic tissues, and a distal, mislocalized anterior organizing center. Moreover, it has not been possible to establish Foxd3−/− ES cell lines or to generate Foxd3−/− teratocarcinomas. Chimera analysis reveals that Foxd3 function is required in the epiblast and that Foxd3−/− embryos can be rescued by a small number of wild-type cells. Foxd3−/− mutant blastocysts appear morphologically normal and express Oct4, Sox2, and Fgf4, but when placed in vitro the inner cell mass initially proliferates and then fails to expand even when Fgf4 is added. These results establish Foxd3 as a factor required for the maintenance of progenitor cells in the mammalian embryo.[Keywords: mouse embryogenesis; stem cells; Foxd3; winged helix gene] Multipotent progenitor cells exist transiently in the mammalian embryo in several tissues including the preimplantation stage blastocyst, the gastrulating epiblast, and the neural crest. Each of these cell types can be cultured in vitro to generate multipotent stem cell lines, and when grafted ectopically, blastocysts and epiblast tissue will produce teratocarcinomas containing multipotent stem cells. Understanding the common molecular regulatory mechanisms of different stem cell types is critical to an understanding of how multipotency is maintained in vivo and how differentiation is controlled.Mammalian embryonic development initiates with a series of cleavage divisions, and at 2.5 days postcoitum (dpc) the free-floating mouse embryo undergoes compaction: cell boundaries become tightly apposed to one another and cells are no longer equivalent. Inner cells contribute to the inner cell mass (ICM) and embryo proper, whereas outer cells contribute to the trophectoderm, a tissue essential for implantation. After implantation, the ICM proliferates and extends distally to form the cuplike egg cylinder (at ∼ 5.5 dpc) consisting of an inner layer of epiblast cells and an outer layer of extraembryonic visceral endoderm (for review, see Hogan et al. 1994).Few genes have been identified that are required for the maintenance of the epiblast cell population and the establishment of ICM-derived embryonic stem (ES) cells in vitro. Oct4−/− embryos, mutant for this POU family transcription factor, die around 5.0 dpc, shortly after implantation but before the egg cylinder is formed. Oct4−/− ES cells cannot be established, as the ICM cells fail to survive (Nichols et al. 1998). Survival of multipotent cells of the ICM is highly sensitive to Oct4 expression levels; low Oct4 levels result in the differentiat...

SummaryZinc deficiency is characterized by an attenuation of growth factor signaling pathways and an amplification of p53 pathways. This outcome is facilitated by hypo-phosphorylation of AKT and ERK secondary to zinc deficiency, which are permissive events to the activation of the intrinsic cell death pathway. Low zinc concentrations provide an environment that is also conducive to the production of reactive oxygen/reactive nitrogen species (ROS/ RNS) and caspase activation. Additionally, during zinc deficiency endogenous survival pathways such as NF-k B are inhibited in their transactivation potential. The above factors contribute to the irreversible commitment of the zinc deficient cell to death. IUBMB Life, 57: 661-670, 2005

Numerous studies support the concept that a major cause of pregnancy complications can be suboptimal embryonic and fetal nutrition. Although the negative effects of diets low in energy on pregnancy outcome are well documented, less clear are the effects of diets that are low in one or more essential micronutrients. However, several observational and intervention studies suggest that diets low in essential vitamins and minerals can pose a significant reproductive risk in diverse human populations. Although maternal nutritional deficiencies typically occur as a result of low dietary intakes of essential nutrients, nutritional deficiencies at the level of the conceptus can arise through multiple mechanisms. Evidence from experimental animals supports the concept that in addition to primary deficiencies, secondary embryonic and fetal nutritional deficiencies can be caused by diverse factors including genetics, maternal disease, toxicant insults and physiological stressors that can trigger a maternal acute phase response. These secondary responses may be significant contributors to the occurrence of birth defects. An implication of the above is that the frequency and severity of pregnancy complications may be reduced through an improvement in the micronutrient status of the mother.

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Approximately 3% of infants born have at least one serious congenital malformation. In the U.S., an average of 10 infants per thousand die before 1 y of life; about half of these deaths can be attributed to birth defects, low birth weight or prematurity. Although the causes of developmental abnormalities are clearly multifactorial in nature, we suggest that a common factor contributing to the occurrence of developmental abnormalities is suboptimal mineral nutrition during embryonic and fetal development. Using zinc and copper as examples, evidence is presented that nutritional deficiencies can rapidly affect the developing conceptus and result in gross structural abnormalities. Deficits of zinc or copper can result in rapid changes in cellular redox balance, tissue oxidative stress, inappropriate patterns of cell death, alterations in the migration of neural crest cells and changes in the expression of key patterning genes. In addition to well-recognized malformations, mineral deficiencies during perinatal development can result in behavioral, immunological and biochemical abnormalities that persist into adulthood. Although these persistent defects can in part be attributed to subtle morphological abnormalities, in other cases they may be secondary to epigenetic or developmental changes in DNA methylation patterns. Epigenetic defects combined with subtle morphological abnormalities can influence an individual's risk for certain chronic diseases and thus influence his or her risk for morbidity and mortality later in life.