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PubMed2000

Neuronal specification in the spinal cord: inductive signals and transcriptional codes.

Neural circuits are assembled with remarkable precision during embryonic development, and the selectivity inherent in their formation helps to define the behavioural repertoire of the mature organism. In the vertebrate central nervous system, this developmental program begins with the differentiation of distinct classes of neurons from progenitor cells located at defined positions within the neural tube. The mechanisms that specify the identity of neural cells have been examined in many regions of the nervous system and reveal a high degree of conservation in the specification of cell fate by key signalling molecules.

Animals↗

PubMed2001

Developmental biology. Lungfish dental pattern conserved for 360 Myr.

Lungfish, the closest living relatives of four-limbed animals, are unique in that adults lack marginal teeth and have to rely on palatal dental plates for crushing food. We have discovered that an identical pattern of tooth development is used to shape these plates in the hatchlings of fossil and living lungfish species that are separated by 360 million years (Myr) of evolution, even though the adults have very different dental forms; the same pattern is also evident in the transient marginal dentition, despite being functional only until the juvenile stage. This remarkable finding indicates that developmental programming for dentition in lungfish is uniform, unique and conserved for all tooth fields.

Animals↗

PubMed1998

A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD.

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homologue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations in independent patients. A 17-bp insertion in the 3'-end of the coding sequence, resulting in a frame shift, occurred in a patient with ASMD and cataracts, and a G-->A substitution, changing a codon for serine into a codon for asparagine, in the 5'-end of the gene occurred in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied. Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

Amino Acid Sequence↗

PubMed1999

A common human skin tumour is caused by activating mutations in beta-catenin.

WNT signalling orchestrates a number of developmental programs. In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family. One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon. Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin, but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations. Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricomas. Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell origin and aetiology of this common human skin tumour. We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells. At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein. This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.

Amino Acid Sequence↗

PubMed2001

Distinct classes of human stem cells that differ in proliferative and self-renewal potential.

The composition of the human hematopoietic stem cell compartment is poorly understood due to the absence of experimental tools with which to characterize the developmental program of individual stem cells. We report here that human stem cells differ markedly in their repopulation capacity and self-renewal potential, as determined using nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice transplanted with retrovirally transduced cord blood stem cells, called SCID-repopulating cells (SRCs). Clonal stem cell analysis based on the identification of unique retroviral integration sites within serial bone marrow aspirates showed that repopulation was generally oligoclonal with extensive variability in the lifespan and proliferative capacity of individual SRCs. Most clones contributed to human cell engraftment for several weeks after transplantation and then disappeared but others appeared later and persisted. Further evidence for stem cell heterogeneity was found in the secondary transplantation capacity of SRCs. These data point to the existence of different classes of human stem cells with variable self-renewal potential and short- or long-term repopulating capacity.

Animals↗

PubMed2002

Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis.

Formation of the vertebrate heart requires a complex interplay of several temporally regulated signalling cascades. In Xenopus laevis, cardiac specification occurs during gastrulation and requires signals from the dorsal lip and underlying endoderm. Among known Xenopus Wnt genes, only Wnt-11 shows a spatiotemporal pattern of expression that correlates with cardiac specification, which indicates that Wnt-11 may be involved in heart development. Here we show, through loss- and gain-of-function experiments, that XWnt-11 is required for heart formation in Xenopus embryos and is sufficient to induce a contractile phenotype in embryonic explants. Treating the mouse embryonic carcinoma stem cell line P19 with murine Wnt-11 conditioned medium triggers cardiogenesis, which indicates that the function of Wnt-11 in heart development has been conserved in higher vertebrates. XWnt-11 mediates this effect by non-canonical Wnt signalling, which is independent of beta-catenin and involves protein kinase C and Jun amino-terminal kinase. Our results indicate that the cardiac developmental program requires non-canonical Wnt signal transduction.

3T3 Cells↗

PubMed2004

Median bundle neurons coordinate behaviours during Drosophila male courtship.

Throughout the animal kingdom the innate nature of basic behaviour routines suggests that the underlying neuronal substrates necessary for their execution are genetically determined and developmentally programmed. Complex innate behaviours require proper timing and ordering of individual component behaviours. In Drosophila melanogaster, analyses of combinations of mutations of the fruitless (fru) gene have shown that male-specific isoforms (Fru(M)) of the Fru transcription factor are necessary for proper execution of all steps of the innate courtship ritual. Here, we eliminate Fru(M) expression in one group of about 60 neurons in the Drosophila central nervous system and observe severely contracted courtship behaviour, including rapid courtship initiation, absence of orienting and tapping, and the simultaneous occurrence of wing vibration, licking and attempted copulation. Our results identify a small group of median bundle neurons, that in wild-type Drosophila appropriately trigger the sequential execution of the component behaviours that constitute the Drosophila courtship ritual.

Animals↗

PubMed2004

A single population of olfactory sensory neurons mediates an innate avoidance behaviour in Drosophila.

All animals exhibit innate behaviours in response to specific sensory stimuli that are likely to result from the activation of developmentally programmed neural circuits. Here we observe that Drosophila exhibit robust avoidance to odours released by stressed flies. Gas chromatography and mass spectrometry identifies one component of this 'Drosophila stress odorant (dSO)' as CO2. CO2 elicits avoidance behaviour, at levels as low as 0.1%. We used two-photon imaging with the Ca2+-sensitive fluorescent protein G-CaMP to map the primary sensory neurons governing avoidance to CO2. CO2 activates only a single glomerulus in the antennal lobe, the V glomerulus; moreover, this glomerulus is not activated by any of 26 other odorants tested. Inhibition of synaptic transmission in sensory neurons that innervate the V glomerulus, using a temperature-sensitive Shibire gene (Shi(ts)), blocks the avoidance response to CO2. Inhibition of synaptic release in the vast majority of other olfactory receptor neurons has no effect on this behaviour. These data demonstrate that the activation of a single population of sensory neurons innervating one glomerulus is responsible for an innate avoidance behaviour in Drosophila.

Air↗

PubMed2006

Nanog promotes transfer of pluripotency after cell fusion.

Through cell fusion, embryonic stem (ES) cells can erase the developmental programming of differentiated cell nuclei and impose pluripotency. Molecules that mediate this conversion should be identifiable in ES cells. One candidate is the variant homeodomain protein Nanog, which has the capacity to entrain undifferentiated ES cell propagation. Here we report that in fusions between ES cells and neural stem (NS) cells, increased levels of Nanog stimulate pluripotent gene activation from the somatic cell genome and enable an up to 200-fold increase in the recovery of hybrid colonies, all of which show ES cell characteristics. Nanog also improves hybrid yield when thymocytes or fibroblasts are fused to ES cells; however, fewer colonies are obtained than from ES x NS cell fusions, consistent with a hierarchical susceptibility to reprogramming among somatic cell types. Notably, for NS x ES cell fusions elevated Nanog enables primary hybrids to develop into ES cell colonies with identical frequency to homotypic ES x ES fusion products. This means that in hybrids, increased Nanog is sufficient for the NS cell epigenome to be reset completely to a state of pluripotency. We conclude that Nanog can orchestrate ES cell machinery to instate pluripotency with an efficiency of up to 100% depending on the differentiation status of the somatic cell.

Animals↗

PubMed2004

The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans.

Temporal control of cell division is critical for proper animal development. To identify mechanisms involved in developmental arrest of cell division, we screened for cell-cycle mutants that disrupt the reproducible pattern of somatic divisions in the nematode C. elegans. Here, we show that the cdc-14 phosphatase is required for the quiescent state of specific precursor cells. Whereas budding yeast Cdc14p is essential for mitotic exit, inactivation of C. elegans cdc-14 resulted in extra divisions in multiple lineages, with no apparent defects in mitosis or cell-fate determination. CDC-14 fused to the green fluorescent protein (GFP-CDC-14) localized dynamically and accumulated in the cytoplasm during G1 phase. Genetic interaction and transgene expression studies suggest that cdc-14 functions upstream of the cki-1 Cip/Kip inhibitor to promote accumulation of CKI-1 in the nucleus. Our data support a model in which CDC-14 promotes a hypophosphorylated and stable form of CKI-1 required for developmentally programmed cell-cycle arrest.

Amino Acid Sequence↗

PubMed2005

Large-scale in vivo flux analysis shows rigidity and suboptimal performance of Bacillus subtilis metabolism.

Qualitative theoretical approaches such as graph theory and stoichiometric analyses are beginning to uncover the architecture and systemic functions of complex metabolic reaction networks. At present, however, only a few, largely unproven quantitative concepts propose functional design principles of the global flux distribution. As operational units of function, molecular fluxes determine the systemic cell phenotype by linking genes, proteins and metabolites to higher-level biological functions. In sharp contrast to other 'omics' analyses, 'fluxome' analysis remained tedious. By large-scale quantification of in vivo flux responses, we identified a robust flux distribution in 137 null mutants of Bacillus subtilis. On its preferred substrate, B. subtilis has suboptimal metabolism because regulators of developmental programs maintain a 'standby' mode that invests substantial resources in anticipation of changing environmental conditions at the expense of optimal growth. Network rigidity and robustness are probably universal functional design principles, whereas the standby mode may be more specific.

Acetyl Coenzyme A↗

PubMed2003

Gene segment selection in V(D)J recombination: accessibility and beyond.

V(D)J recombination assembles genes encoding antigen receptors according to defined developmental programs in immature B and T lymphocytes. The 'accessibility hypothesis' was initially invoked to explain how a single recombinase complex could control the locus and allele specificity of V(D)J recombination. It has been since shown that recombination signal sequences themselves influence recombination efficiency and specificity in ways that had not been previously appreciated. Recent developments have increased our understanding of how the chromatin barrier to V(D)J recombination is regulated, and how chromatin control and the properties of the underlying recombination signal sequences may cooperate to create diverse, lineage-restricted and allelically excluded repertoires of antigen receptors.

Alleles↗

PubMed2006

Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment.

Hematopoiesis requires tight regulation of the hematopoietic stem cell (HSC) population; however, the dynamics of HSC use at steady state are uncertain. Over 3-7 months, we evaluated the repopulation and self-renewal of more than 600 individual human 'severe combined immunodeficiency mouse-repopulating cells' (SRCs), tracked on the basis of lentiviral integration sites, in serially transplanted immune-deficient mice, as well as of SRC daughter cells that migrated to different marrow locations in a single mouse. Our data demonstrate maintenance by self-renewing SRCs after an initial period of clonal instability, a result inconsistent with the clonal succession model. We found wide variation in proliferation kinetics and self-renewal among SRCs, as well as between SRC daughter cells that repopulated equivalently, suggesting that SRC fate is unpredictable before SRCs enter more rigid 'downstream' developmental programs.

ADP-ribosyl Cyclase 1↗

PubMed2002

The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansion.

Mice deficient in the adaptor protein SLP-65 (also known as BLNK) have reduced numbers of mature B cells, but an increased pre-B cell compartment. We show here that compared to wild-type cells, SLP-65(-/-) pre-B cells show an enhanced ex vivo proliferative capacity. This proliferation requires interleukin 7 and expression of the pre-B cell receptor (pre-BCR). In addition, SLP-65(-/-) mice have a high incidence of pre-B cell lymphoma. Reintroduction of SLP-65 into SLP-65(-/-) pre-B cells led to pre-BCR down-regulation and enhanced differentiation. Our results indicate that SLP-65 regulates a developmental program that promotes differentiation and limits pre-B cell expansion, thereby acting as a tumor suppressor.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Similarities and differences in CD4+ and CD8+ effector and memory T cell generation.

Naive CD4+ and CD8+ T cells undergo unique developmental programs after activation, resulting in the generation of effector and long-lived memory T cells. Recent evidence indicates that both cell-intrinsic and cell-extrinsic factors regulate memory T cell differentiation. This review compares and contrasts how naive CD4+ and CD8+ T cells make the transition to effector and/or memory cells and discusses the implications of these findings for vaccine development.

Animals↗

PubMed2001

Electrical activity and development of neural circuits.

A distinct feature of the nervous system is the intricate network of synaptic connections among neurons of diverse phenotypes. Although initial connections are formed largely through molecular mechanisms that depend on intrinsic developmental programs, spontaneous and experience-driven electrical activities in the developing brain exert critical epigenetic influence on synaptic maturation and refinement of neural circuits. Selective findings discussed here illustrate some of our current understanding of the effects of electrical activity on circuit development and highlight areas that await further study.

Action Potentials↗

PubMed2025

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

Humans↗

PubMed2000

Ceramide selectively inhibits apoptosis-associated events in NGF-deprived sympathetic neurons.

Ceramide manifests both neurotoxic and neuroprotective properties depending on the experimental system. Ito and Horigome previously reported that ceramide delays apoptosis in a classic model of developmental programmed cell death, i.e. sympathetic neurons undergoing NGF deprivation.1 Here, we investigated the actions of ceramide upon the biochemical and genetic changes that occur in NGF deprived neurons. We correlate ceramide's neuroprotective actions with the ability of ceramide to antagonize NGF deprivation-induced oxidative stress and c-jun induction, both of which contribute to apoptosis in this model. However, ceramide did not block NGF deprivation-induced declines in RNA and protein synthesis, suggesting that ceramide does not slow all apoptosis-related events. Overall, these results are significant in that they show that ceramide acts early in the death cascade to antagonize two events necessary for NGF-deprivation induced neuronal apoptosis. Moreover, these results dissociate declines in neuronal function, i.e. macromolecular synthesis, from the neuronal death cascade.

Animals↗