Attenuation of FGF signalling in mouse beta-cells leads to diabetes

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.     

Initiation of neural induction by FGF signalling before gastrulation

During neural induction, the 'organizer' of the vertebrate embryo instructs neighbouring ectodermal cells to become nervous system rather than epidermis. This process is generally thought to occur around the mid-gastrula stage of embryogenesis. Here we report the isolation of ERNI, an early response gene to signals from the organizer (Hensen's node). Using ERNI as a marker, we present evidence that neural induction begins before gastrulation--much earlier in development than previously thought. We show that the organizer and some of its precursor cells produce a fibroblast growth factor signal, which can initiate, and is required for, neural induction.     

Nodal signalling in vertebrate development

Communication between cells during early embryogenesis establishes the basic organization of the vertebrate body plan. Recent work suggests that a signalling pathway centering on Nodal, a transforming growth factor beta-related signal, is responsible for many of the events that configure the vertebrate embryo. The activity of Nodal signals is regulated extracellularly by EGF-CFC cofactors and antagonists of the Lefty and Cerberus families of proteins, allowing precise control of mesoderm and endoderm formation, the positioning of the anterior-posterior axis, neural patterning and left-right axis specification.     

Feedback control of intercellular signalling in development

The intercellular communication that regulates cell fate during animal development must be precisely controlled to avoid dangerous errors. How is this achieved? Recent work has highlighted the importance of positive and negative feedback loops in the dynamic regulation of developmental signalling. These feedback interactions can impart precision, robustness and versatility to intercellular signals. Feedback failure can cause disease.     

Specification of limb development in the Drosophila embryo by positional cues from segmentation genes

Limb development in Drosophila requires the activity of a proximo-distal pattern-forming system, in addition to the antero-posterior and dorso-ventral pattern-forming systems that subdivide the embryo. Several lines of genetic evidence indicate that the Distal-less gene plays an important part in specifying proximo-distal positional information. The Distal-less locus encodes a homoeodomain-containing protein, which suggests that Distal-less may exert its activity through differential regulation of subordinate genes. The spatially restricted pattern of Distal-less expression allows direct visualization of the limb primordia during early embryogenesis. Here I report that from their inception, the leg primordia span the parasegment boundary. The segment polarity gene wingless seems to have a key part in defining the positions at which leg primordia will develop along the antero-posterior axis of the embryo. This analysis allows a direct molecular visualization of the compartments that subdivide the limb primordia into discrete developmental domains.     

Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds.

Outgrowth and patterning of the vertebrate limb are controlled by reciprocal interactions between the posterior mesenchyme (polarizing region) and a specialized ectodermal structure, the apical ectodermal ridge (AER). Sonic hedgehog (SHH) signalling by the polarizing region modulates fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop). Here we report that the secreted bone-morphogenetic-protein (BMP) antagonist Gremlin relays the SHH signal from the polarizing region to the AER. Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (Id) mutation, which disrupts establishment of the SHH/FGF4 feedback loop. Grafting Gremlin-expressing cells into ld mutant limb buds rescues Fgf4 expression and restores the SHH/FGF4 feedback loop. Analysis of Shh-null mutant embryos reveals that SHH signalling is required for maintenance of Gremlin and Formin (the gene disrupted by the ld mutations). In contrast, Formin, Gremlin and Fgf4 activation are independent of SHH signalling. This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish the SHH/FGF4 feedback loop.     

Gene defect in ectodermal dysplasia implicates a death domain adapter in development.

Members of the tumour-necrosis factor receptor (TNFR) family that contain an intracellular death domain initiate signalling by recruiting cytoplasmic death domain adapter proteins. Edar is a death domain protein of the TNFR family that is required for the development of hair, teeth and other ectodermal derivatives. Mutations in Edar-or its ligand, Eda-cause hypohidrotic ectodermal dysplasia in humans and mice. This disorder is characterized by sparse hair, a lack of sweat glands and malformation of teeth. Here we report the identification of a death domain adapter encoded by the mouse crinkled locus. The crinkled mutant has an hypohidrotic ectodermal dysplasia phenotype identical to that of the edar (downless) and eda (Tabby) mutants. This adapter, which we have called Edaradd (for Edar-associated death domain), interacts with the death domain of Edar and links the receptor to downstream signalling pathways. We also identify a missense mutation in its human orthologue, EDARADD, that is present in a family affected with hypohidrotic ectodermal dysplasia. Our findings show that the death receptor/adapter signalling mechanism is conserved in developmental, as well as apoptotic, signalling.     

Discovery of very-high-energy gamma-rays from the Galactic Centre ridge

The source of Galactic cosmic rays (with energies up to 10(15) eV) remains unclear, although it is widely believed that they originate in the shock waves of expanding supernova remnants. At present the best way to investigate their acceleration and propagation is by observing the gamma-rays produced when cosmic rays interact with interstellar gas. Here we report observations of an extended region of very-high-energy (> 10(11) eV) gamma-ray emission correlated spatially with a complex of giant molecular clouds in the central 200 parsecs of the Milky Way. The hardness of the gamma-ray spectrum and the conditions in those molecular clouds indicate that the cosmic rays giving rise to the gamma-rays are likely to be protons and nuclei rather than electrons. The energy associated with the cosmic rays could have come from a single supernova explosion around 10(4) years ago.     

Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development

The vertebrate limb initially develops as a bud of mesenchymal cells that subsequently aggregate in a proximal to distal (P-D) sequence to give rise to cartilage condensations that prefigure all limb skeletal components. Of the three cardinal limb axes, the mechanisms that lead to establishment and patterning of skeletal elements along the P-D axis are the least understood. Here we identify a genetic interaction between Gli3 (GLI-Kruppel family member 3) and Plzf (promyelocytic leukaemia zinc finger, also known as Zbtb16 and Zfp145), which is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot are relatively unperturbed in Gli3(-/-);Plzf(-/-) mouse embryos. We demonstrate that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb-bud independently of known P-D patterning markers and overall limb-bud size. Moreover, the limb defects in Gli3(-/-);Plzf(-/-) embryos correlate with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor, type 1B (Bmpr1b) at the onset of limb development. These findings suggest that the development of proximal and distal skeletal elements is distinctly regulated early during limb-bud formation. The initial division of the vertebrate limb into two distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins.     

Multiple intercellular signalling systems control the development of the Caenorhabditis elegans vulva.

Developmental, genetic and molecular studies indicate that multiple intercellular signalling systems interact to specify the types and spatial patterns of cells generated during the formation of the vulva of the nematode Caenorhabditis elegans. Two classes of evolutionarily conserved transmembrane receptors and a Ras protein function in these signalling systems. The biology of vulval development provides a framework for understanding how cell interactions control the development of animals as diverse as nematodes, insects and mammals.     

A re-examination of proximodistal patterning during vertebrate limb development

The 'progress zone' model provides a framework for understanding progressive development of the vertebrate limb. This model holds that undifferentiated cells in a zone of fixed size at the distal tip of the limb bud (the progress zone) undergo a progressive change in positional information such that their specification is altered from more proximal to more distal fates. This positional change is thought to be driven by an internal clock that is kept active as long as the cells remain in the progress zone. However, owing to cell division, the most proximal of these cells are continually pushed outside the confines of the zone. As they exit, clock function ceases and cells become fixed with the positional value last attained while within the zone. In contrast to this model, our data suggest that the various limb segments are 'specified' early in limb development as distinct domains, with subsequent development involving expansion of these progenitor populations before differentiation. We also find, however, that the distal limb mesenchyme becomes progressively 'determined', that is, irreversibly fixed, to a progressively limited range of potential proximodistal fates.     

Deciphering skeletal patterning: clues from the limb

Even young children can distinguish a Tyrannosaurus rex from a Brontosaurus by observing differences in bone size, shape, number and arrangement, that is, skeletal pattern. But despite our extensive knowledge about cartilage and bone formation per se, it is still largely a mystery how skeletal pattern is established. Much of what we do know has been learned from studying limb development in chicken and mouse embryos. Based on the data from such studies, models for how limb skeletal pattern is established have been proposed and continue to be hotly debated.     

Distal-less encodes a homoeodomain protein required for limb development in Drosophila

The spatial organization of the Drosophila embryo depends on the activity of three axial pattern-forming systems. In addition to the anterior-posterior and dorsal-ventral systems that organize the segmented body plan, a proximal-distal pattern-forming system is required to provide positional information for the developing limbs. The development of both the larval and adult limbs depends directly on the activity of the Distal-less gene. Genetic analysis has shown that Distal-less functions as a developmental switch that is required to promote the development of limb structures above the evolutionary ground-state of body wall. Here we provide genetic evidence that indicates a graded requirement for Distal-less activity during limb development. Reduction of this activity has a global effect on pattern formation in the limb. The molecular structure of the Distal-less locus indicates that the gene encodes a homoeodomain-containing protein which is therefore likely to specify limb development through differential regulation of subordinate genes.     

Homeobox gene expression correlated with the bifurcation process of limb cartilage development.

The complex architecture of the limb cartilage pattern probably develops by the sequential segmentation and branching process of precartilaginous cell condensation under the control of positional signalling provided by the zone of polarizing activity (anteroposterior) and the apical ectodermal ridge (proximodistal). This signalling is monitored and interpreted in the mesenchymal cells and induces the position-specific response of subsets of genes. Homeobox genes may be responsible for the interpretation of signalling. A correlation between limb pattern and expression domains of the homeobox genes in the upstream region of Hox/Chox-4 has been proposed. We have analysed the spatial expression pattern of the Chox-1 genes during development of chick limb buds. In contrast to genes in Hox/Chox-4 expressed coordinately along the anteroposterior axis, homeobox genes in Chox-1 have unique and mutually exclusive expression domains along the proximodistal axis. We report here that the expression domains of the Chox-1 genes are closely related to the segmental structure of cartilage along the proximodistal axis, whereas the expression domains of the Chox-4 genes are related to the cartilage branching pattern.     

夸克集团模型对胶子分布函数的核效应的解释

利用夸克集团模型，适当给定核内存在６夸克集团及９夸克集团的几率，很好地解释了胶子分布函数的核效应     

Mox2 is a component of the genetic hierarchy controlling limb muscle development.

The skeletal muscles of the limbs develop from myogenic progenitors that originate in the paraxial mesoderm and migrate into the limb-bud mesenchyme. Among the genes known to be important for muscle development in mammalian embryos are those encoding the basic helix-loop-helix (bHLH) myogenic regulatory factors (MRFs; MyoD, Myf5, myogenin and MRF4) and Pax3, a paired-type homeobox gene that is critical for the development of limb musculature. Mox1 and Mox2 are closely related homeobox genes that are expressed in overlapping patterns in the paraxial mesoderm and its derivatives. Here we show that mice homozygous for a null mutation of Mox2 have a developmental defect of the limb musculature, characterized by an overall reduction in muscle mass and elimination of specific muscles. Mox2 is not needed for the migration of myogenic precursors into the limb bud, but it is essential for normal appendicular muscle formation and for the normal regulation of myogenic genes, as demonstrated by the downregulation of Pax3 and Myf5 but not MyoD in Mox2-deficient limb buds. Our findings show that the MOX2 homeoprotein is an important regulator of vertebrate limb myogenesis.