Trends in developmental biology最新文献

Epigenetic modifications to DNA and its associated proteins affect cell plasticity and cell fate restrictions throughout embryonic development. Development of the vertebrate pancreas is characterized by initial is an over-lapping expression of a set of transcriptional regulators in a defined region of the posterior foregut endoderm that collectively promote pancreas progenitor specification and proliferation. As development progresses, these transcription factors segregate into distinct pancreatic lineages, with some being maintained in specific subsets of terminally differentiated pancreas cell types throughout adulthood. Here we describe the progressive stages and cell fate restrictions that occur during pancreas development and the relevant known epigenetic regulatory events that drive the dynamic expression patterns of transcription factors that regulate pancreas development. In addition, we highlight how changes in epigenetic marks can affect susceptibility to pancreas diseases (such as diabetes), adult pancreas cell plasticity, and the ability to derive replacement insulin-producing β cells for the treatment of diabetes.

A fundamental question in developmental biology is how a single genome gives rise to the diversity of cell fates. In essence, each cell fate in the human body is a unique but stable output state of the genome, maintained by positive and negative feedbacks from both inside and outside the cell (a stable cell state). Traditionally, defining a cell fate means identifying a unique combination of transcriptional factors expressed by the specific cell type. The hundreds of transcriptional factors in the genome, however, have complicated the task of simplifying cell fate representation and obtaining insights into its regulation. Moreover, results from this approach provides only a mostly static picture, with each cell fate/state disconnected from one another. An alternative approach instead defines cell fates by determining their relationship to each other, through identifying the signaling pathways that control each step of their lineage transition from a common progenitor during development. Decades of studies have shown only a handful of signaling pathways are sufficient to specify all cell fates in the body, simplifying the execution of such a strategy. In this review, I will argue this alternative approach is not only feasible but also has the potential of simplifying the cell fate landscape as well as facilitating the engineering of different cell fates for regenerative medicine.

Fertilization in mammals is initiated by species-restricted binding of free-swimming sperm to the unfertilized egg's thick extracellular matrix, the zona pellucida (ZP). Both acrosome-intact and acrosome-reacted sperm can bind to the ZP, but only the latter can penetrate the ZP, reach the egg's plasma membrane, and fuse with plasma membrane (fertilization) to produce a zygote. Following fertilization, the ZP is modified by cortical granule components such that acrosome-intact and acrosome-reacted sperm are unable to bind to fertilized eggs. Here we review some of the evidence that bears directly on the involvement of two mouse ZP proteins, mZP2 and mZP3, as receptors for binding of mouse sperm to unfertilized eggs and address some contentious issues surrounding this important initial step in the process of mammalian fertilization.

According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, the intrauterine environment influences fetal programming and development, affecting offspring disease susceptibility in adulthood. In recent years, therapeutic use of the Type 2 diabetes drug metformin has expanded to the treatment of pre-diabetes, polycystic ovarian syndrome, and gestational diabetes. Because metformin both undergoes renal excretion and binds to receptors on the placenta, the fetus receives equivalent maternal dosing. Although no teratogenic nor short-term harmful fetal impact of metformin is known to occur, the effects of metformin exposure on longer-range offspring development have not yet been fully elucidated. This review encapsulates the (albeit limited) existing knowledge regarding the potential longer-term impact of intrauterine metformin exposure on the development of key organs including the liver, central nervous system, heart, gut, and endocrine pancreas in animal models and humans. We discuss molecular and cellular mechanisms that would be altered in response to treatment and describe the potential consequences of these developmental changes on postnatal health. Further studies regarding the influence of metformin exposure on fetal programming and adult metabolic health will provide necessary insight to its long-term risks, benefits, and limitations in order to guide decisions for use of metformin during pregnancy.

A gestation length of normal duration and natural delivery at term are considered to be important indicators of a healthy pregnancy, especially given the potentially adverse consequences for neonates of being born premature. While many have assessed the factors influencing gestation length in humans, and there has been considerable interest in the pregnancy duration of domesticated farm animals, this topic has not been re-assessed recently in rhesus monkeys, the most commonly used primate in biomedical research. In older articles, it's gestation length was typically reported to be 165 days, although most authors acknowledged that viable pregnancies could occur out to 180 days. Predicting the normal range of acceptable due dates has important veterinary implications for when to intervene in a prolonged pregnancy. Using archival records from a large, established breeding program, gestation lengths and infant birthweights were analyzed for 408 pregnancies across a 25-year period. The potential influence of maternal factors, including age and parity, was assessed. Familial concordance in gestation length within mother-daughter matrilines was examined, as well as similarity in length across repeat pregnancies for 84 multiparous females. Mean duration from mating to delivery was 168.8 days, longer than reported in most but not all previous articles. Many females birthed successfully at a longer duration that might have prompted consideration of a caesarian delivery. Gestation length for an individual female was fairly stable and significantly correlated across multiple pregnancies. There was not a pronounced transgenerational influence on gestation length even though familial propensities for birthing small and large infants were evident in the female descendants. Typical pregnancy lengths and birthweights are provided as reference norms to assist other breeding programs and to enhance our understanding of the natural reproduction of rhesus macaques that still live in many forested and urban locations across South Asia.

The zona pellucida (ZP) is an extracellular matrix (ECM) that surrounds all mammalian oocytes, eggs, and embryos and plays vital roles during oogenesis, fertilization, and preimplantation development. The mouse and human ZP is composed of three or four unique proteins, respectively, called ZP1-4, that are synthesized, processed, and secreted by oocytes during their growth phase. All ZP proteins have a zona pellucida domain (ZPD) that consists of ≈270 amino acids and has 8 conserved Cys residues present as four intramolecular disulfides. Secreted ZP proteins assemble into long fibrils around growing oocytes with ZP2-ZP3 dimers located periodically along the fibrils. The fibrils are cross-linked by ZP1 to form a thick, transparent ECM to which sperm must first bind and then penetrate during fertilization of eggs. Inactivation of mouse ZP1, ZP2, or ZP3 by gene targeting affects both ZP formation around oocytes and fertility. Female mice with eggs that lack a ZP due to inactivation of either ZP2 or ZP3 are completely infertile, whereas inactivation of ZP1 results in construction of an abnormal ZP and reduced fertility. Results of a large number of studies of infertile female patients strongly suggest that gene sequence variations (GSV) in human ZP1, ZP2, or ZP3 due to point, missense, or frameshift mutations have similar deleterious effects on ZP formation and female fertility. These findings are discussed in light of our current knowledge of ZP protein synthesis, processing, secretion, and assembly.

Birth weight (BW) at delivery is an important developmental milestone indicative of prenatal conditions and portends of the postnatal growth trajectory that will occur during infancy and childhood. Previous research has documented that there are also many physiological and health consequences of being born either small-for-gestational age (SGA) or large-for-gestational age (LGA). Analyses of breeding animals have demonstrated further that a gravid female exerts a strong influence on the size of her infant by term, and this permissiveness or constraint over fetal growth can be transmitted from mothers to their daughters. The following research tested additional hypotheses about matrilineal effects on BW by examining records from a large breeding colony of rhesus monkeys across multiple generations. The analyses utilized BW of 1710 infant monkeys obtained over 4 decades. In addition to determining the association between the birth weight (BW) of a female and her own infants birthed later as a mother, the multi-generational transmission of birth size from a grandmother through her daughters to the next generation was examined. Other maternal influences were evident, including a progressive increase in infant BW with parity, which synergized with matrilineal effects across a female's reproductive life. In addition, our modeling indicated that if an infant's BW was discordant-a SGA female birthing a larger daughter-the discrepant fetal growth pattern could be accentuated in the next generation. Overall, the findings confirm that the size of an infant at term is significantly influenced by a type of gestational imprinting on daughters during the prenatal period, which then continues to shape birth outcomes in subsequent generations.

Mutations in cytochrome P450 1B1 (CYP1B1) gene are reported in patients with primary congenital glaucoma. Cyp1b1-deficient (Cyp1b1-/-) mice show dysgenesis of the trabecular meshwork (TM) tissue and attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy (OIR). Although retinal vascular cells, including endothelial cells (EC), pericytes (PC), astrocytes (AC), and TM endothelial cells express CYP1B1, the cell autonomous contribution of CYP1B1 to attenuation of retinal neovascularization and TM tissue dysgenesis remains unknown. Here we determined the impact lack of CYP1B1 expression in EC, PC or AC has on retinal neovascularization and TM tissue integrity. We generated Cyp1b1-transgenic mice with vascular cell-specific targeted Cre⁺-deletion in EC (Cyp1b1 ^EC), in PC (Cyp1b1 ^PC) and in AC (Cyp1b1 ^AC). Pathologic retinal neovascularization during OIR was evaluated by collagen IV staining of retinal wholemounts. Structural morphology of TM tissue was examined by transmission electron microscopy (TEM). The assessment of retinal neovascularization indicated a significant decrease in retinal neovascular tufts only in Cyp1b1 ^PC mice compared with control mice. TEM evaluation demonstrated Cyp1b1 ^PC mice also exhibited a defect in TM tissue morphology and integrity similar to that reported in Cyp1b1-/- mice. Thus, Cyp1b1 expression in PC plays a significant role in retinal neovascularization and the integrity of TM tissue.

The process of taking a piece of tissue and transplanting it into a novel location has been of paramount importance for life sciences. The technique of transplantation has served an important role in providing a basic understanding of all facets of biology ranging from cancer and evolutionary biology to developmental biology. First employed by early embryologists, transplantation has played a particularly critical role in elucidating virtually every aspect of embryonic development including cell specification, commitment, cell fate determination, embryonic induction, and plasticity. This review will detail the essential role cell transplantation experiments have played in uncovering fundamental developmental and cell biological processes as well as their valuable contribution to contemporary developmental biology. Finally, it will suggest fruitful directions that this technique, in conjunction with current molecular and sequencing technologies, could play in future work.

The Developmental Origins of Health and Disease (DOHaD) Hypothesis postulates that the in utero environment influences postnatal health and plays a role in disease etiology. Studies in both humans and animal models have shown that exposure to either under- or overnutrition in utero results in an increased risk of metabolic disease later in life. In addition, offspring born to overweight or obese mothers are more likely to be obese as children and into early adulthood and to have impaired glucose tolerance as adults. The Centers for Disease Control and Prevention estimates that over 70% of adults over the age of 20 are either overweight or obese and that nearly half of women are either overweight or obese at the time they become pregnant. Thus, the consequences of maternal overnutrition on the developing fetus are likely to be realized in greater numbers in the coming decades. This review will focus specifically on the effects of in utero overnutrition on pancreatic islet development and function and how the resulting morphological and functional changes influence the offspring's risk of developing metabolic disease. We will discuss the advantages and challenges of different animal models, the effects of exposure to overnutrition during distinct periods of development, the similarities and differences between and within model systems, and potential mechanisms and future directions in understanding how developmental alterations due to maternal diet exposure influence islet health and function later in life.