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Results for “Developmental programming”

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PubMed1994

Temporal and lineage-specific control of T cell receptor alpha/delta gene rearrangement by T cell receptor alpha and delta enhancers.

To analyze the regulation of gene rearrangement at the T cell receptor (TCR) alpha/delta locus during T cell development, we generated transgenic mice carrying a human TCR delta gene minilocus. We previously showed that the presence of the TCR delta enhancer (E delta) within the J delta 3-C delta intron was required to activate a specific step (V-D to J) of transgene rearrangement, and that rearrangement was activated equivalently in the precursors of alpha beta and gamma delta T cells. To further explore the role of transcriptional enhancers in establishing the developmental pattern of gene rearrangement at the TCR alpha/delta locus, we substituted the TCR alpha enhancer (E alpha) in place of E delta within the transgenic minilocus. We found that V-D-J rearrangement of the E alpha+ minilocus was restricted to the alpha beta T cell subset. Further, we found that although V-D-J rearrangement of the E delta+ minilocus was initiated in the fetal thymus by day 14.5, V-D-J rearrangement of the E alpha+ minilocus did not occur until fetal day 16.5. Finally, whereas V-D-J rearrangement of the E delta+ minilocus is essentially completed within the triple negative population of postnatal thymocytes, V-D-J rearrangement of the E alpha+ minilocus is only initiated late within this population. Since the properties of minilocus rearrangement under the control of E delta and E alpha parallel the properties of V delta-D delta-J delta and V alpha-J alpha rearrangement at the endogenous TCR alpha/delta locus, we conclude that these enhancers play an important role in orchestrating the developmental program of rearrangements at this locus.

Animals↗

PubMed1996

Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.

Neonatal thymectomy (NTx), especially around day 3 after birth, causes various organ-specific autoimmune diseases in mice. This report shows that: (a) T cells expressing the interleukin 2 receptor alpha chains (CD25) ontogenically begin to appear in the normal periphery immediately after day 3, rapidly increasing within 2 wk to nearly adult levels (approximately 10% of CD3+ cells, especially of CD4+ cells); (b) NTx on day 3 eliminates CD25+ T cells from the periphery for several days; inoculation immediately after NTx of CD25+ splenic T cells from syngeneic non-Tx adult mice prevents autoimmune development, whereas inoculation of CD25- T cells even at a larger dose does not; and furthermore, (c) similar autoimmune diseases can be produced in adult athymic nu/nu mice by inoculating either spleen cell suspensions from 3-d-old euthymic nu/+ mice or CD25+ cell-depleted spleen cell suspensions from older, even 1-yr-old, nu/+ mice. The CD25- populations from neonates or adults are also similar in the profile of cytokine formation. These results, taken together, indicate that one aspect of peripheral self-tolerance is maintained by CD25+ T cells that sustain potentially pathogenic self-reactive T cells in a CD25- dormant state; the thymic production of the former is developmentally programmed to begin on day 3 after birth in mice. Thus, NTx on day 3 can, at least transiently, eliminate/reduce the autoimmune-preventive CD25+ T cells, thereby leading to activation of the self-reactive T cells that have been produced before NTx.

Age Factors↗

PubMed2003

Ligand-dependent inhibition of CD1d-restricted NKT cell development in mice transgenic for the activating receptor Ly49D.

In addition to their CD1d-restricted T cell receptor (TCR), natural killer T (NKT) cells express various receptors normally associated with NK cells thought to act, in part, as modulators of TCR signaling. Immunoreceptor-tyrosine activation (ITAM) and inhibition (ITIM) motifs associated with NK receptors may augment or attenuate perceived TCR signals respectively, potentially influencing NKT cell development and function. ITIM-containing Ly49 family receptors expressed by NKT cells are proposed to play a role in their development and function. We have produced mice transgenic for the ITAM-associated Ly49D and ITIM-containing Ly49A receptors and their common ligand H2-Dd to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-Dd transgenic mice had selectively and severely reduced numbers of thymic and peripheral NKT cells, whereas both ligand and Ly49D transgenics had normal numbers of NKT cells. CD1d tetramer staining revealed a blockade of NKT cell development at an early precursor stage. Coexpression of a Ly49A transgene partially rescued NKT cell development in Ly49D/H2-Dd transgenics, presumably due to attenuation of ITAM signaling. Thus, Ly49D-induced ITAM signaling is incompatible with the early development of cells expressing semi-invariant CD1d-restricted TCRs and appropriately harmonized ITIM-ITAM signaling is likely to play an important role in the developmental program of NKT cells.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice.

The differentiation of CD4(+) CD8(+) double positive (DP) thymocytes requires the irreversible choice between two alternative lineages, distinguished by the mutually exclusive expression of either CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8, and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization, we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predicted by the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains. These data provide evidence that lineage-specific developmental programs are established early during the transition from the DP to the single positive stage.

Alleles↗

PubMed2005

Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor-induced Nur77 expression and apoptosis.

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH(2) terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection.

Active Transport, Cell Nucleus↗

PubMed2005

Contrasting models of promiscuous gene expression by thymic epithelium.

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model-whereby TRA expression is regulated by conserved developmental programs active in developing mTECs-may be equally plausible.

Animals↗

PubMed2000

Primary autosomal recessive microcephaly: MCPH5 maps to 1q25-q32.

Primary microcephaly is thought to result from genetic defects of the developmental program that generates large brain hemispheres in humans. Autosomal recessive inheritance is likely in most familial cases, and four loci were recently mapped by homozygosity. We report homozygosity mapping of a new locus, MCPH5, with a maximum multipoint LOD score of 3.51 at marker D1S1723, in a family of Turkish origin. The minimal critical region spans 11.4 cM between markers D1S384 and D1S2655, at 1q25-q32, and encompasses the cytogenetic breakpoints of chromosomal aberrations previously reported in unrelated patients with microcephaly.

Adult↗

PubMed2002

A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease.

Hirschsprung disease (HSCR) is a common genetic disorder characterized by intestinal obstruction secondary to enteric aganglionosis. HSCR demonstrates a complex pattern of inheritance, with the RET proto-oncogene acting as a major gene and with several additional susceptibility loci related to the Ret-signaling pathway or to other developmental programs of neural crest cells. To test how the HSCR phenotype may be affected by the presence of genetic variants, we investigated the role of a single-nucleotide polymorphism (SNP), 2508C-->T (S836S), in exon 14 of the RET gene, characterized by low frequency among patients with HSCR and overrepresentation in individuals affected by sporadic medullary thyroid carcinoma. Typing of several different markers across the RET gene demonstrated that a whole conserved haplotype displayed anomalous distribution and nonrandom segregation in families with HSCR. We provide genetic evidence about a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrate a possible functional effect linked to RET messenger RNA expression.

Alleles↗

PubMed2005

Differential X reactivation in human placental cells: implications for reversal of X inactivation.

X inactivation--the mammalian method of X chromosome dosage compensation--is extremely stable in human somatic cells; only fetal germ cells have a developmental program to reverse the process. The human placenta, at term, differs from other somatic tissues, since it has the ability to reverse the X-inactivation program. To determine whether reversal can be induced at other stages of placental development, we examined earlier placental specimens using a cell-hybridization assay. We found that global X reactivation is also inducible in villi cells from first-trimester spontaneous abortions but not from first-trimester elective terminations. These differences in inducibility are not associated with detectable variation in histone H4 acetylation, DNA methylation, or XIST expression--hallmarks of the inactivation process--so other factors must have a role. One notable feature is that the permissive cells, unlike nonpermissive ones, have ceased to proliferate in vivo and are either beginning or in the process of programmed cell death. Cessation of mitotic proliferation also characterizes oocytes at the stage at which they undergo X reactivation. We suggest that, along with undermethylation, the apoptotic changes accompanying cessation of cell proliferation contribute to the reversal of inactivation, not only in placental cells, but also in oocytes entering meiosis.

Acetylation↗

PubMed2006

Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans.

Congenital primary aphakia (CPA) is a rare developmental disorder characterized by the absence of lens, the development of which is normally induced during the 4th-5th wk of human embryogenesis. This original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histological criterion for CPA. So far, the genetic basis for this human condition has remained unclear. Here, we present the analysis of a consanguineous family with three siblings who had bilateral aphakia, microphthalmia, and complete agenesis of the ocular anterior segment. We show that a null mutation in the FOXE3 gene segregates and, in the homozygous state, produces the mutant phenotype in this family. Therefore, this study identifies--to our knowledge, for the first time--a causative gene for CPA in humans. Furthermore, it indicates a possible critical role for FOXE3 very early in the lens developmental program, perhaps earlier than any role recognized elsewhere for this gene.

Adult↗

PubMed1999

Parthenogenetic activation of porcine oocytes after nuclear transfer.

Mature porcine oocytes are arrested at metaphase II of meiosis. At fertilization, like all mammalian oocytes they exhibit a low frequency Ca(2+) oscillation lasting several hours. This oscillation is thought to be the signal that triggers resumption of meiosis and activates the developmental program of the oocyte. The signal transduction mechanism of the sperm-induced Ca(2+) signal is not known in detail, and attempts to generate the oscillation artificially have met with little success. Nevertheless, artificial activation of the oocyte is a crucial step during nuclear transfer. Methods are available to induce a transient elevation in the intracellular free Ca(2+) concentration to surpass the meiotic arrest and induce development of the constructed embryo. Further studies concentrating on the mechanism of Ca(2+) signaling during fertilization will help to improve the efficiency of the procedures used for parthenogenetic activation of the oocyte.

Journal Article↗

PubMedDate not supplied

Specific cytosine demethylations within the first exons of the rat CYP2D3 and CYP2D5 genes are associated with activation of hepatic gene expression during development.

To investigate the mechanism of transcriptional activation of the CYP2D gene subfamily in rat liver during development, Northern blot analysis and DNA methylation tests using Hpa II and Hha I enzymes, which are sensitive to cytosine methylated DNA, were carried out. As the result of mRNA measurements, these genes were classified into two patterns of expression, (i) late-onset gene activation in which mRNA gradually increases until rats reach puberty and (ii) early-onset expression in which the peak of mRNA expression is reached within 1 week after birth. The CYP2D3 and CYP2D5 genes, representatives of late-onset and early-onset expression, respectively, were examined. A correlation was found between mRNA expression during development and demethylation of cytosine residues located at the same position in the first exons of both the CYP2D3 and CYP2D5 genes. These results suggest that specific demethylation events are associated with developmentally programmed hepatic gene activation.

Animals↗

PubMed1992

Characterization of liver-enriched proteins binding to a developmentally demethylated site flanking the avian apoVLDLII gene.

Although the avian apoVLDLII gene is normally expressed exclusively in the liver of the laying hen, the gene can be activated by estrogen in birds of either sex beginning between days 7-9 of embryogenesis. Developmentally programmed demethylation of sites in the 5'- and 3'-flanking regions of the gene have been shown to occur during this period of embryogenesis, suggesting that they may reflect changes in protein-DNA interactions that are involved in the acquisition of competence to activate the apoVLDLII gene. We have detected specific protein interactions at one location approximately 2.6 kb upstream from the apoVLDLII gene, that includes an Msp I site whose methylation status changes between days 7 and 9 of embryogenesis. The sequence of this region bears significant similarity to binding sites of members of the bZIP family of liver-enriched or -specific factors such as C/EBP, DBP, and LAP, that are characteristically produced relatively late during liver development. In the studies described here, we demonstrate that proteins binding to the upstream apoVLDLII site do not correspond to previously identified liver-enriched or -specific factors. They also display a pattern of activity during development and in human and avian hepatoma cell lines indicating that their expression is increased in proliferating cells. Southwestern blotting and UV cross-linking studies indicate that two proteins of approximately 60 kD are capable of binding to the site and we describe the purification of these factors from crude nuclear protein extracts obtained from rooster liver.

Animals↗

PubMed1994

Complete structure and expression of the rat alpha B-crystallin gene.

alpha B-Crystallin, a member of the small heat shock family of proteins, is synthesized as a component of various developmental programs, in response to stress and in a number of pathological states. We have determined the complete structure of the alpha B-crystallin gene (6,806 bp encompassing 2,299 bp upstream from ATG and 859 bp at the 3' end, past the first polyadenylation signal). Comparison of the rat and the human alpha B-crystallin genes reveals significant conservation of the nucleotide sequences in almost all regions except in intron 2. The 1-kb region immediately upstream of ATG shows about 75% overall homology. A 78-bp sequence in the intron 1 and sequences in the 3' untranslated region show about 95% and 85% sequence identity, respectively. Characterization of the expression of this gene in different tissues in the rat by extensive analyses, utilizing primer extension. RNase protection, and rapid amplification of cDNA ends (RACE) revealed a predominant transcription initiation site 44 bp upstream of ATG. Northern analyses with "coding-only" and upstream "noncoding" probes did not support the thesis that heterogeneity in the alpha B-crystallin mRNAs arises from variations in the sequences immediately upstream of the predominant transcription initiation site. Importantly, the known relative levels of alpha B-crystallin protein in different tissues correlate best with the presence of transcripts starting from this initiation site.

Amino Acid Sequence↗

PubMed1998

Enhanced green fluorescent protein as an efficient reporter gene for retroviral transduction of human multipotent lymphoid precursors.

Owing to its autofluorescence properties, green fluorescent protein (GFP) has aroused increasing interest as a marker system for many research applications. In this study we investigated the suitability of the "enhanced" GFP (EGFP), a mutant version of GFP optimized for flow cytometry and microscopy detection, as a reporter gene for retroviral transduction protocols. EGFP was shown to display a bright and stably maintained emission pattern in transfected GP+envAm12 packaging cells. Stable fluorescent emission was observed as well after transduction in NIH 3T3 fibroblasts and in the human Jurkat T cell line, in which EGFP was shown to confer no deleterious effect or growth disadvantage on the expressing cells. Moreover, EGFP expression could be detected after short-term retroviral exposure, thus allowing a rapid and quantitative retroviral titering assay, alternative to the standard colony-formation procedure. Most importantly, we showed the feasibility of EGFP as a marker gene in retroviral-mediated transduction of primary lymphoid precursors. In particular, transduction of CD34+CD1- human thymocytes by short-term cocultivation yielded up to 30% of EGFP-expressing cells, while maintaining CD34 expression levels. Finally, when cultured under multicytokine-supported conditions, such transduced intrathymic progenitors were shown to efficiently generate lymphoid-related dendritic cells, which displayed a distinct EGFP expression. Therefore, because of its rapid and easy detectability and its nontoxic characteristics, EGFP proves itself to be a valuable reporter gene by allowing the transduction of multipotential progenitors and by being compatible with the developmental programs of lymphoid lineage generation.

3T3 Cells↗

PubMed2001

Ggamma in dictyostelium: its role in localization of gbetagamma to the membrane is required for chemotaxis in shallow gradients.

G-protein-mediated signal transduction pathways play an essential role in the developmental program of the simple eukaryotic organism Dictyostelium discoideum. Database searches have yielded 11 Galpha-subunits, a single Gbeta-subunit, but no Ggamma-subunits. We report here the purification, cDNA isolation, and functional analysis of a Ggamma-subunit. Like Gbeta, the Ggamma appears to be unique and hybridization studies show that Ggamma and Gbeta are expressed in parallel during development. Species-wide sequence comparisons of Ggamma-subunits and gamma-like domains of RGS proteins reveal short stretches of highly conserved residues as well as the common CXXL motif at the COOH-terminal of Ggammas that target Gbetagammas to plasma membrane. Overexpression of a CSVL-deleted Ggamma (GgammaDelta) in wild-type cells shifts Gbetagamma to the cytosol and selectively impairs certain G-protein-mediated signal transduction pathways. These cells are able to respond to increments in the stimulus, but are unable to sense chemoattractant gradients. They neither move directionally nor recruit PH-domains to their leading edge. Thus, a full complement of membrane-tethered Gbetagamma is required for sensing shallow gradients, but is not essential for responses to increments in extracellular stimuli.

Animals↗

PubMed2002

Mitochondrial development during life cycle differentiation of African trypanosomes: evidence for a kinetoplast-dependent differentiation control point.

Life cycle differentiation of African trypanosomes entails developmental regulation of mitochondrial activity. This requires regulation of the nuclear genome and the kinetoplast, the trypanosome's unusual mitochondrial genome. To investigate the potential cross talk between the nuclear and mitochondrial genome during the events of differentiation, we have 1) disrupted expression of a nuclear-encoded component of the cytochrome oxidase (COX) complex; and 2) generated dyskinetoplastid cells, which lack a mitochondrial genome. Using RNA interference (RNAi) and by disrupting the nuclear COX VI gene, we demonstrate independent regulation of COX component mRNAs encoded in the nucleus and kinetoplast. However, two independent approaches (acriflavine treatment and RNA interference ablation of mitochondrial topoisomerase II) failed to establish clonal lines of dyskinetoplastid bloodstream forms. Nevertheless, dyskinetoplastid forms generated in vivo could undergo two life cycle differentiation events: transition from bloodstream slender to stumpy forms and the initiation of transformation to procyclic forms. However, they subsequently arrested at a specific point in this developmental program before cell cycle reentry. These results provide strong evidence for a requirement for kinetoplast DNA in the bloodstream and for a kinetoplast-dependent control point during differentiation to procyclic forms.

Acriflavine↗

PubMed2003

Role of integrins in the development of the cerebral cortex.

Spatial and temporal changes in expression and function of integrin receptors in the developing cerebral wall parallel neurogenesis, radial glial differentiation, neuronal migration and the emergence of neuronal layers in the cerebral cortex. The distinct outcomes of integrin and extracellular matrix ligand mutations underscore the dynamic role they play in these processes during corticogenesis. The changing patterns of adhesive interactions mediated by integrins and their ligands across the cerebral wall during embryogenesis may set in motion developmental programs needed for progressive acquisition of different neuronal or glial phenotypes in the cerebral cortex. Here we discuss the role of integrins during cortical layer formation.

Animals↗