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PubMed1996

The Dictyostelium MAP kinase ERK2 regulates multiple, independent developmental pathways.

We showed previously that the MAP kinase ERK2 is essential for aggregation. erk2 null cells lack cAMP stimulation of adenylyl cyclase and thus cannot relay the cAMP chemotactic signal, although the cells chemotax to cAMP (Segall et al. 1995). In this paper we have examined the role of ERK2 in controlling developmental gene expression and morphogenesis during the multicellular stages, making use of a temperature-sensitive ERK2 mutation. Using suspension assays, we show that ERK2 is not essential for aggregation-stage, cAMP pulse-induced gene expression, or for the expression of postaggregative genes, which are induced at the onset of mound formation in response to cAMP in wild-type cells. In contrast, the prespore-specific gene SP60 is not induced and the prestalk-specific gene ecmA is induced but at a significantly reduced level. Chimeric organisms, comprised of wild-type and erk2 null cells expressing the prestalk-specific ecmA/lacZ reporter, show an abnormal spatial patterning, in which Erk2ts/erk2 cells are excluded from the very anterior prestalk A region. To further examine the function of ERK2 during the multicellular stages, we bypassed the requirement of ERK2 for aggregation by creating an ERK2 temperature-sensitive mutant. erk2 null cells expressing the ERK2ts mutant develop normally at 20 degrees C and express cell-type-specific genes but do not aggregate at temperatures above 25 degrees C. Using temperature shift experiments, we showed that ERK2 is essential for proper morphogenesis and for the induction and maintenance of prespore but not prestalk gene expression. Our results indicate that ERK2 functions at independent stages during Dictyostelium development to control distinct developmental programs: during aggregation, ERK2 is required for the activation of adenylyl cyclase and during multicellular development, ERK2 is essential for morphogenesis and cell-type-specific gene expression. Analysis of these results and other supports the conclusion that the requirement of ERK2 for cell-type differentiation is independent of its role in the activation of adenylyl cyclase.

Amino Acid Sequence↗

PubMed2003

The role of class I HLH genes in neural development--have they been overlooked?

Helix-loop-helix (HLH) genes encode for transcription factors affecting a whole variety of developmental programs, including neurogenesis. At least seven functional classes (denoted I to VII) of HLH genes exist, (1) with subclass members exhibiting homo- and heterodimerisation for proper DNA binding and transcriptional regulation of downstream target genes. In the developing nervous system, members of class II, V and VI have been most extensively studied concerning their roles in neural programming. In contrast, the function of class I proteins (such as E12 and E47) is poorly defined and the orthodox view relegates them to general dimerisation duties that are necessary for the activity of the other classes. However, closer scrutiny of the spatiotemporal expression patterns of class I factors, combined with recent biochemical evidence, would suggest that class I proteins possess specific functions during early neural differentiation. This essay supports this possibility, in addition to putting forward the hypothesis that, outside their general dimerisation activity, class I genes have independent roles in regulating neurogenesis.

Animals↗

PubMed1995

Gnot1, a member of a new homeobox gene subfamily, is expressed in a dynamic, region-specific domain along the proximodistal axis of the developing limb.

Limb development endures as an excellent model for pattern formation in vertebrates. We have identified Gnot1 as a member of a new homeobox gene subfamily. Gnot1 is expressed in a dynamic temporospatial distribution in the developing limb, initially correlating with regions destined to form distal structures and then becoming progressively more restricted to specific regions determined to give rise to wrist and ankle. Micro-surgical alteration of the developmental program of the limb reveals that Gnot1 is expressed in a position- and fate-dependent manner, responding both to signals from the apical ridge and the polarizing zone. Furthermore, Gnot1 activation by polarizing signals occurs temporally downstream of Hoxd gene activation, but well before the first appearance of condensations that will give rise to the carpus of the wrist. The features of Gnot1 expression suggest a role for this gene in regulating pattern formation during limb development.

Age Factors↗

PubMed1997

Mutational analysis of the early forespore/mother-cell signalling pathway in Bacillus subtilis.

Intercellular communication is a crucial phenomenon during spore development in Bacillus subtilis. It couples the establishment of a compartment-specific genetic program to the transcriptional activity of a sigma factor in the other compartment. It also keeps sigma factor activation in register with the morphological process. This study used directed mutagenesis to analyse the pathway that couples sigma E activation in the mother-cell to activation of sigma F in the forespore following asymmetric septation. Targets for mutagenesis in SpoIIGA (the receptor) were chosen based on the predicted topology of the protein when associated with the cell membrane. The results showed that a residue near the N terminus (D6), predicted to be exposed outside the cell, is required for receptor activity, whereas the major extracellular loop (between membrane domains IV and V) is dispensable for function. In contrast, mutations in SpoIIR (the signal) that partially blocked protein release (but not membrane translocation) had no effect on signal transduction. These results do not rule out the possibility that uncharacterized molecules intervene in the signalling pathway that establishes the mother-cell-specific developmental program during the early stage of sporulation.

Alkaline Phosphatase↗

PubMed2005

KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo.

The Krüppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins that are important in controlling developmental programs. Erythroid Krüppel-like factor (EKLF or KLF1) positively regulates the beta-globin gene in definitive erythroid cells. KLF2 (LKLF) is closely related to EKLF and is expressed in erythroid cells. KLF2-/- mice die between embryonic day 12.5 (E12.5) and E14.5, because of severe intraembryonic hemorrhaging. They also display growth retardation and anemia. We investigated the expression of the beta-like globin genes in KLF2 knockout mice. Our results show that KLF2-/- mice have a significant reduction of murine embryonic Ey- and beta h1-globin but not zeta-globin gene expression in the E10.5 yolk sac, compared with wild-type mice. The expression of the adult beta(maj)- and beta(min)-globin genes is unaffected in the fetal livers of E12.5 embryos. In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic epsilon-globin gene but not the adult beta-globin gene, suggesting that this developmental-stage-specific role is evolutionarily conserved. KLF2 also plays a role in the maturation and/or stability of erythroid cells in the yolk sac. KLF2-/- embryos have a significantly increased number of primitive erythroid cells undergoing apoptotic cell death.

Animals↗

PubMed1997

Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action.

Previously we observed that stable clones of multipotent neural progenitor cells, initially isolated and propagated from the external granular layer of newborn wild-type mouse cerebellum, could participate appropriately in cerebellar development when reimplanted into the external granular layer of normal mice. Donor cells could reintegrate and differentiate into neurons (including granule cells) and/or glia consistent with their site of engraftment. These findings suggested that progenitors might be useful for cellular replacement in models of aberrant neural development or neurodegeneration. We tested this hypothesis by implanting clonally related multipotent progenitors into the external granular layer of newborn meander tail mice (gene symbol=mea). mea is an autosomal recessive mutation characterized principally by the failure of granule cells to develop in the cerebellar anterior lobe; the mechanism is unknown. We report that approximately 75% of progenitors transplanted into the granuloprival anterior lobe of neonatal mea mutants differentiated into granule cells, partially replacing or augmenting that largely absent neuronal population in the internal granular layer of the mature meander tail anterior lobe. (The ostensibly 'normal' meander tail posterior lobe also benefited from repletion of a more subtle granule cell deficiency.) Donor-derived neurons were well-integrated within the neuropil, suggesting that these progenitors' developmental programs for granule cell differentiation were unperturbed. These observations permitted several conclusions. (1) That exogenous progenitors could survive transplantation into affected regions of neonatal meander tail cerebellum and differentiate into the deficient cell type suggested that the microenvironment was not inimical to granule cell development. Rather it suggested that mea's deleterious action is intrinsic to the external granular layer cell. (Any cell-extrinsic actions--albeit unlikely--had to be restricted to readily circumventable prenatal events.) This study, therefore, offers a paradigm for using progenitors to help determine the site of action of other mutant genes or to test hypotheses regarding the pathophysiology underlying other anomalies. (2) In the regions most deficient in neurons, a neuronal phenotype was pursued in preference to other potential cell types, suggesting a 'push' of undifferentiated, multipotent progenitors towards compensation for granule cell dearth. These data suggested that progenitors with the potential for multiple fates might differentiate towards repletion of deficient cell types, a possible developmental mechanism with therapeutic implications. Neural progenitors (donor or endogenous) might enable cell replacement in some developmental or degenerative diseases--most obviously in cases where a defect is intrinsic to the diseased cell, but also, under certain circumstances, when extrinsic pathologic forces may exist.

Animals↗

PubMed1995

Layer-specific programs of development in neocortical projection neurons.

How are long-range axonal projections from the cerebral cortex orchestrated during development? By using both passively and actively transported axonal tracers in fetal and postnatal ferrets, we have analyzed the development of projections from the cortex to a number of thalamic nuclei. We report that the projections of a cortical area to its corresponding thalamic nuclei follow highly cell-specific programs of development. Axons from cells in the deepest layers of the cerebral cortex (layer 6 and superficial subplate neurons) appear to grow very slowly and be delayed for several weeks in the cerebral white matter, reaching the thalamus over a protracted period. Neurons of layer 5, on the other hand, develop their projections much faster; despite being born after the neurons of deeper layers, layer 5 neurons are the first to extend their axons out of the cortical hemisphere and innervate the thalamus. Layer 5 projections are massive in the first postnatal weeks but may become partly eliminated later in development, being overtaken in number by layer 6 cells that constitute the major corticothalamic projection by adulthood. Layer 5 projections are area-specific from the outset and arise as collateral branches of axons directed to the brainstem and spinal cord. Our findings show that the early development of corticofugal connections is determined not by the sequence of cortical neurogenesis but by developmental programs specific for each type of projection neuron. In addition, they demonstrate that in most thalamic nuclei, layer 5 neurons (and not subplate or layer 6 neurons) establish the first descending projections from the cerebral cortex.

Animals↗

PubMed2004

Generation of reelin-positive marginal zone cells from the caudomedial wall of telencephalic vesicles.

An early and fundamental step of the laminar organization of developing neocortex is controlled by the developmental programs that critically depend on the activities of reelin-positive cells in the marginal zone. However, the ontogeny of reelin-positive cells remained elusive. To gain insights into the spatial and temporal regulation of reelin-positive marginal zone cell development, we used a transgenic mouse line in which we defined the green fluorescent protein (GFP) transgene as a novel reliable molecular marker of reelin-positive marginal zone cells from the early stages of their development. We further used exo utero electroporation-mediated gene transfer that allows us to mark progenitor cells and monitor the descendants in the telencephalon in vivo. We show here the generation of reelin-positive marginal zone cells from the caudomedial wall of telencephalic vesicles, including the cortical hem, where the prominent expression of GFP is initially detected. These neurons tangentially migrate at the cortical marginal zone and are distributed throughout the entire neocortex in a caudomedial-high to rostrolateral-low gradient during the dynamic developmental period of corticogenesis. Therefore, our findings on reelin-positive marginal zone cells, in addition to the cortical interneurons, add to the emerging view that the neocortex consists of neuronal subtypes that originate from a focal source extrinsic to the neocortex, migrate tangentially into the neocortex, and thereby underlie neural organization of the neocortex.

Animals↗

PubMed1976

RNase sensitivity of an anterior morphogenetic determinant in an insect egg (Smittia sp., Chironomidae, Diptera).

In chironomid midges, the development of head and thorax in the embryo requires the function of cytoplasmic determinants localized near the anterior pole of the egg. Experimental inactivation of these determinants causes a dramatic switch in the developmental program of the embryo. Instead of the normal segment pattern, the aberrant pattern "double abdomen" is formed. Head, thorax, and anterior abdominal segments are then replaced by an additional set of posterior abdominal segments joined in mirror image symmetry to the original abdomen. Such double abdomens have been produced, with a maximum yield of 29%, by application of RNase (ribonuclease I, ribonucleate 3'-pyrimidino-oligonucleotidohydrolase, EC 3.1.4.22) to the anterior pole region of the egg. This was achieved by microinjection or puncturing the eggs during submersion in RNase. Control experiments with inactive RNase S fragments reliably proved that double abdomen formation resulted from RNase activity. Neither application of other enzymes to the anterior pole region nor application of RNase to other egg regions produced double abdomens in significant yields. The effects of RNase concentration and stage of development were determined. The data from these and earlier experiments are compatible with the idea that stored cytoplasmic RNP particles act as anterior determinants. Similarities to genetically caused switches in developmental pathways (homeotic mutations) are discussed.

Age Factors↗

PubMedDate not supplied

Social work in a dental program for the developmentally disabled.

This article discusses the role of a social worker in a dental school based program for the developmentally disabled. Developmentally disabled people constitute a heterogeneous population with problems that often prevent them from receiving appropriate dental services. A social worker in the dental care setting can help this population access dental services. Data gathered during a 2-year period support the hypothesis that patients living at home present more obstacles to dental care and require more social work intervention in obtaining dental care than patients living in residential settings.

Dental Care for Persons with Disabilities↗

PubMed1999

Germline development in vertebrates and invertebrates.

In all animals information is passed from parent to offspring via the germline, which segregates from the soma early in development and undergoes a complex developmental program to give rise to the adult gametes. Many aspects of germline development have been conserved throughout the animal kingdom. Here we review the unique properties of germ cells, the initial determination of germ cell fates, the maintenance of germ cell identity, the migration of germ cells to the somatic gonadal primordia and the proliferation of germ cells during development invertebrates and invertebrates. Similarities in germline development in such diverse organisms as Drosophila melanogaster, Caenorhabditis elegans, Xenopus laevis and Mus musculus will be highlighted.

Animals↗

PubMed1993

Developmentally regulated changes in 1,2-diacylglycerol in Dictyostelium. Regulation by light and G proteins.

We have measured 1,2-diacylglycerol (DG) mass during Dictyostelium development. DG levels are initially high in vegetative cells, decrease upon starvation, increase during aggregation, and rise dramatically during culmination, concomitant with SpiA (a spore cell-specific gene) expression. These results are consistent with DG being involved in culmination-stage morphological changes and cell-type differentiation. Mutant analysis shows that the rise in DG during aggregation requires cAMP signaling pathways but is not directly regulated through these processes but via developmental programs induced through cAMP. DG accumulation during aggregation is approximately 8-fold higher than would be expected from inositol lipid hydrolysis (1), suggesting that DG is produced from sources in addition to phosphatidylinositol 4,5-bisphosphate. Our data suggest that during aggregation, although some DG is formed through phospholipase D activity, other pathways (e.g. de novo synthesis) may be more important regulators of DG accumulation. During culmination, DG accumulation correlated with the formation of phosphatidic acid and phosphatidylethanol suggesting the activation of phospholipase D. During this time, the [3H]palmitate labeling of a number of phospholipids decreased rapidly, suggesting a rapid metabolism of phospholipids at this time. Exposure of slugs developed in the dark to light, which initiates culmination, causes rapid DG accumulation, suggesting the activation of phospholipid hydrolysis. The temporal pattern and level of DG accumulation is altered in G alpha 1 null and overexpressing strains, suggesting that G alpha 1 is upstream from DG formation during culmination. These results demonstrate that specific pathways of DG formation are under developmental control and suggest a possible link between light, the activation of DG production, and induction of culmination.

Animals↗

PubMed2006

Pancreas and beta-cell development: from the actual to the possible.

The development of insulin-producing pancreatic beta (beta)-cells represents the culmination of a complex developmental program. Cells of the posterior foregut assume a pancreatic identity, cells within the expanding pancreatic primordia adopt an endocrine fate, and a subset of these precursors becomes competent to generate beta-cells. Postnatally, beta-cells are primarily maintained by self-duplication rather than new differentiation. Although major gaps in our knowledge still persist, experiments across several organisms have shed increasing light on the steps of beta-cell specification and differentiation. Increasing our understanding of the extrinsic, as well as intrinsic, mechanisms that control these processes should facilitate efforts to regenerate this important cell type in humans.

Animals↗

PubMed2007

Embryology and genetics of primary vesico-ureteric reflux and associated renal dysplasia.

Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.

Animals↗

PubMed1996

The sea pansy Renilla reniformis luciferase serves as a sensitive bioluminescent reporter for differential gene expression in Candida albicans.

The infectious yeast Candida albicans progresses through two developmental programs which involve differential gene expression, the bud-hypha transition and high-frequency phenotypic switching. To understand how differentially expressed genes are regulated in this organism, the promoters of phase-specific genes must be functionally characterized, and a bioluminescent reporter system would facilitate such characterization. However, C. albicans has adopted a nontraditional codon strategy that involves a tRNA with a CAG anticodon to decode the codon CUG as serine rather than leucine. Since the luciferase gene of the sea pansy Renilla reinformis contains no CUGs, we have used it to develop a highly sensitive bioluminescent reporter system for C. albicans. When fused to the galactose-inducible promoter of GAL1, luciferase activity is inducible; when fused to the constitutive EF1 alpha 2 promoter, luciferase activity is constitutive; and when fused to the promoter of the white-phase-specific gene WH11 or the opaque-phase-specific gene OP4, luciferase activity is phase specific. The Renilla luciferase system can, therefore, be used as a bioluminescent reporter to analyze the strength and developmental regulation of C. albicans promoters.

Animals↗

PubMed2005

Remodeling dendrites during insect metamorphosis.

The genesis of dendritic shape during development sets in place key characteristics of a neuron's physiology and connectivity. During this construction, a cell interprets intrinsic cell-specific developmental programs and cues from the environment to generate its final phenotype. In insects that undergo complete metamorphosis certain neurons function in the larval nervous system and then remodel to generate an adult-specific arbor. By studying the dendrites of neurons that undergo such a cellular metamorphosis, one can explore the mechanisms that underlie both stereotyped pruning and local remodeling. Live imaging techniques in intact Drosophila have been especially useful in examining the outgrowth of the adult-specific dendritic arbors in remodeling dendritic arborizing (da) sensory neurons. These neurons show an initial scaffold-building phase during which the cell establishes the overall shape of the arbor and then switch to an elaboration phase where the arbor is filled out with higher order branches. The cellular machinery employed during these two phases is different, with branch retraction being a prominent feature of the scaffold building phase but absent from the elaboration phase. The transition between these two modes does not appear to be "hard-wired" but is plastic and under the extrinsic control of developmental hormones. This transition in branch dynamics may also involve changes in calcium signaling in the growing arbor. The potential relationship between hormone-induced transcriptional change and the calcium dynamics in dendritic morphogenesis is discussed.

Animals↗

PubMed2005

Evolution of insect metamorphosis: a microarray-based study of larval and adult gene expression in the ant Camponotus festinatus.

Holometabolous insects inhabit almost every terrestrial ecosystem. The evolutionary success of holometabolous insects stems partly from their developmental program, which includes discrete larval and adult stages. To gain an understanding of how development differs among holometabolous insect taxa, we used cDNA microarray technology to examine differences in gene expression between larval and adult Camponotus festinatus ants. We then compared expression patterns obtained from our study to those observed in the fruitfly Drosophila melanogaster. We found that many genes showed distinct patterns of expression between the larval and adult ant life stages, a result that was confirmed through quantitative reverse-transcriptase polymerase chain reaction. Genes involved in protein metabolism and possessing structural activity tended to be more highly expressed in larval than adult ants. In contrast, genes relatively upregulated in adults possessed a greater diversity of functions and activities. We also discovered that patterns of expression observed for homologous genes in D. melanogaster differed substantially from those observed in C. festinatus. Our results suggest that the specific molecular mechanisms involved in metamorphosis will differ substantially between insect taxa. Systematic investigation of gene expression during development of other taxa will provide additional information on how developmental pathways evolve.

Animals↗

PubMed2003

Maternal factors in zebrafish development.

All processes that occur before the activation of the zygotic genome at the midblastula transition are driven by maternal products, which are produced during oogenesis and stored in the mature oocyte. Upon egg activation and fertilization, these maternal factors initiate developmental cascades that carry out the embryonic developmental program. Even after the initiation of zygotic gene expression, perduring maternal products continue performing essential functions, either together with other maternal factors or through interactions with newly expressed zygotic products. Advances in zebrafish research have placed this organism in a unique position to contribute to a detailed understanding of the role of maternal factors in early vertebrate development. This review summarizes our knowledge on the processes involved in the production and redistribution of maternal factors during zebrafish oogenesis and early development, as well as our understanding of the function of these factors in axis formation, germ layer and germ cell specification, and other early embryonic processes.

Animals↗