Mechanisms of Development最新文献

The antagonism between Mdm2 and its close homolog Mdm4 (also known as MdmX) and p53 is vital for embryogenesis and organogenesis. Previously, we demonstrated that targeted disruption of Mdm2 in the Hoxb7+ ureteric bud (Ub) lineage, which gives rise to the renal collecting system, causes renal hypodysplasia culminating in perinatal lethality. In this study, we examine the unique role of Mdm4 in establishing the collecting duct system of the murine kidney. Hoxb7Cre driven loss of Mdm4 in the Ub lineage (Ub^Mdm4−/−) disrupts branching morphogenesis and triggers UB cell apoptosis. Ub^Mdm4−/− kidneys exhibit abnormally dilated Ub tips while the medulla is hypoplastic. These structural alterations result in secondary depletion of nephron progenitors and nascent nephrons. As a result, newborn Ub^Mdm4−/− mice have hypo-dysplastic kidneys. Transcriptional profiling revealed downregulation of the Ret-tyrosine kinase pathway components, Gdnf, Wnt11, Sox8, Etv4 and Cxcr4 in the Ub^Mdm4−/− mice relative to controls. Moreover, the expression levels of the canonical Wnt signaling members Axin2 and Wnt9b are downregulated. Mdm4 deletion upregulated p53 activity and p53-target gene expression including Cdkn1a (p21), Gdf15, Ccng1, PERP, and Fas. Germline loss of p53 in Ub^Mdm4−/− mice largely rescues kidney development and terminal differentiation of the collecting duct. We conclude that Mdm4 plays a unique and vital role in Ub branching morphogenesis and collecting system development.

Gastrulation is generally understood as the morphogenetic processes that result in the spatial organization of the blastomere into the three germ layers, ectoderm, mesoderm and endoderm. This review summarizes our current knowledge of the morphogenetic mechanisms in Drosophila gastrulation. In addition to the events that drive mesoderm invagination and germband elongation, we pay particular attention to other, less well-known mechanisms including midgut invagination, cephalic furrow formation, dorsal fold formation, and mesoderm layer formation. This review covers topics ranging from the identification and functional characterization of developmental and morphogenetic control genes to the analysis of the physical properties of cells and tissues and the control of cell and tissue mechanics of the morphogenetic movements in the gastrula.

Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1–13 hpf (early) and 25–37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 μM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 μM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.

Among the basally branching metazoans, cnidarians display well-defined gastrulation processes leading to a diploblastic body plan, consisting of an endodermal and an ectodermal cell layer. As the outgroup to all Bilateria, cnidarians are an interesting group to investigate ancestral developmental mechanisms. Interestingly, all known gastrulation mechanisms known in Bilateria are already found in different species of Cnidaria. Here I review the morphogenetic processes found in different Cnidaria and focus on the investigation of the cellular and molecular mechanisms in the sea anemone Nematostella vectensis, which has been a major model organism among cnidarians for evolutionary developmental biology. Many of the genes involved in germ layer specification and morphogenetic processes in Bilateria are also found active during gastrulation of Nematostella and other cnidarians, suggesting an ancestral role of this process. The molecular analyses indicate a tight link between gastrulation and axis patterning processes by Wnt and FGF signaling. Interestingly, the endodermal layer displays many features of the mesodermal layer in Bilateria, while the pharyngeal ectoderm has an endodermal expression profile. Comparative analyses as well as experimental studies using embryonic aggregates suggest that minor differences in the gene regulatory networks allow the embryo to transition relatively easily from one mode of gastrulation to another.

‘Developmental robustness’ is the ability of biological systems to maintain a stable phenotype despite genetic, environmental or physiological perturbations. In holometabolous insects, accurate patterning and development is guaranteed by alignment of final gene expression patterns in tissues at specific developmental stage such as molting and pupariation, irrespective of individual rate of development. In the present study, we used faster developing Drosophila melanogaster populations that show reduction of ~22% in egg to adult development time. Flies from the faster developing population exhibit phenotype constancy, although significantly small in size. The reduction in development time in faster developing flies is possibly due to coordination between higher ecdysteroid release and higher expression of developmental genes. The two together might be ensuring appropriate pattern formation and early exit at each development stage in the populations selected for faster pre-adult development compared to their ancestral controls. We report that apart from plasticity in the rate of pattern progression, alteration in the level of gene expression may be responsible for pattern integrity even under reduced development time.

Gastrulation consists in the dramatic reorganisation of the epiblast, a one-cell thick epithelial sheet, into a multilayered embryo. In chick, the formation of the internal layers requires the generation of a macroscopic convection-like flow, which involves up to 50,000 epithelial cells in the epiblast. These cell movements locate the mesendoderm precursors into the midline of the epiblast to form the primitive streak. There they acquire a mesenchymal phenotype, ingress into the embryo and migrate outward to populate the inner embryonic layers. This review covers what is currently understood about how cell behaviours ultimately cause these morphogenetic events and how they are regulated. We discuss 1) how the biochemical patterning of the embryo before gastrulation creates compartments of differential cell behaviours, 2) how the global epithelial flows arise from the coordinated actions of individual cells, 3) how the cells delaminate individually from the epiblast during the ingression, and 4) how cells move after the ingression following stereotypical migration routes. We conclude by exploring new technical advances that will facilitate future research in the chick model system.

All pancreatic cell populations arise from the standard gut endoderm layer in developing embryos, requiring a regulatory gene network to originate and maintain endocrine lineages and endocrine function. The pancreatic organogenesis is regulated by the temporal expression of transcription factors and plays a diverse role in the specification, development, differentiation, maturation, and functional maintenance. Altered expression and activity of these transcription factors are often associated with diabetes mellitus. Recent advancements in the stem cells and invitro derived islets to treat diabetes mellitus has attracted a great deal of interest in the understanding of factors regulating the development, differentiation, and functions of islets including transcription factors. This review discusses the myriad of transcription factors regulating the development of the pancreas, differentiation of β-islets, and how these factors regulated in normal and disease states. Exploring these factors in such critical context and exogenous or endogenous expression of development and differentiation-specific transcription factors with improved epigenetic plasticity/signaling axis in diabetic milieu would useful for the development of β-cells from other cell sources.

Little is known about the molecular mechanisms underlying alveolar development. P311, a putative neuronal protein originally identified for its high expression during neuronal development, has once been reported to play a potential role in distal lung generation. However, the function of this protein has been poorly understood so far. Hence, we carried out a yeast two-hybrid screen, combining with other protein-protein interaction experiments, to isolate several binding partners of P311 during lung development, which may help us explore its function. We report 7 proteins here, including Gal-1, Loxl-1 and SPARC, etc, that can interact with it. Most of them have similar spatio-temporal expression patterns to P311. In addition, it was also found that P311 could stimulate their expression indirectly in L929 mouse fibroblast. Besides, computational methods were applied to construct a P311 centered protein-protein interaction network during alveolarization, using the 7 binding partners and their protein interaction information provided by public data resources. By analyzing the structure and function of this network, the effects of P311 on lung development were further clarified and all of the bioinformatic predictions from the network could be validated by real experiments. We have found here that P311 can control lung redox events, extracellular matrix and cell cycle progression, which are all crucial to pulmonary morphogenesis. This gives us a novel thought to explore the mechanisms controlling alveolarization.

During mouse embryonic development a mass of pluripotent epiblast tissue is transformed during gastrulation to generate the three definitive germ layers: endoderm, mesoderm, and ectoderm. During gastrulation, a spatiotemporally controlled sequence of events results in the generation of organ progenitors and positions them in a stereotypical fashion throughout the embryo. Key to the correct specification and differentiation of these cell fates is the establishment of an axial coordinate system along with the integration of multiple signals by individual epiblast cells to produce distinct outcomes. These signaling domains evolve as the anterior-posterior axis is established and the embryo grows in size. Gastrulation is initiated at the posteriorly positioned primitive streak, from which nascent mesoderm and endoderm progenitors ingress and begin to diversify. Advances in technology have facilitated the elaboration of landmark findings that originally described the epiblast fate map and signaling pathways required to execute those fates. Here we will discuss the current state of the field and reflect on how our understanding has shifted in recent years.

The aging process is closely related to the organization of stem cells, and skin is thought to be one of the suitable models for its investigation. We have focused on the murine hair follicle to verify this idea because it shows typical aging phenotypes and is a self-renewing structure reconstituted by its own stem cells. However, how changes in the characteristics of the hair follicle and in the behavior of tissue stem cells in the natural hair cycle occur are not fully understood. We investigated the number, morphology and pigmentation of hair follicles in anagen phases during the aging process. In addition, stem cells for keratinocytes and melanocytes were examined to evaluate the correlation between changes in skin characteristics and the stem cells. The remarkable changes caused by aging appeared to be the significant increase in qualitative phenotypes such as curved hair follicles and white hair. A significant difference between the number of keratinocyte and melanocyte stem cells in the hair bulge region is likely to be involved in these changes. Our findings may be important for understanding the mechanisms of the actions of stem cells on hair regeneration and for clarifying the mechanisms of age-related phenotypes.