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PubMed2003

Developmental gene network analysis.

The developmental process is controlled by the information processing functions executed by the cis-elements that regulate the expression of the participating genes. A model of the network of cis-regulatory interactions that underlies the specification of the endomesoderm of the sea urchin embryo is analyzed here. Although not all the relevant interactions have yet been uncovered, the model shows how the information processing functions executed by the cis-regulatory elements involved can control essential functions of the specification process, such as transforming the localization of maternal factors into a domain-specific program of gene expression; refining the specification pattern; and stabilizing states of specification. The analysis suggests that the progressivity of the developmental process is also controlled by the cis-regulatory interactions unraveled by the network model. Given that evolution occurs by changing the program for development of the body plan, we illustrate the potential of developmental gene network analysis in understanding the process by which morphological features are maintained and diversify. Comparison of the network of cis-regulatory interactions with a portion of that underlying the specification of the endomesoderm of the starfish illustrates how the similarities and differences provide insights into how the programs for development work and how they evolve.

Animals↗
PubMed2005

Midkine regulates pleiotrophin organ-specific gene expression: evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family.

Midkine (MK) and the highly related cytokine pleiotrophin (PTN) constitute the PTN/MK developmental gene family. The Mk and Ptn genes are essential for normal development of the catecholamine and renin-angiotensin pathways and the synthesis of different collagens. It is not known whether the Ptn and Mk genes regulate each other or whether PTN and MK are functionally redundant in development. We have now compared the levels of expression of Ptn and Mk in genetically deficient Mk -/- and Ptn -/- mice and found highly significant increases in Ptn gene expression in spinal cord, dorsal root ganglia, eye, heart, aorta, bladder, and urethra, but not in brain, bone marrow, testis, and lung of Mk -/- mice compared with wild type mice; a remarkable approximately 230-fold increase in Ptn expression levels was found in heart of Mk -/- mice and highly significant but lesser increases were found in six other organs. Differences in levels of Mk gene expression in Ptn -/- mice could not be detected in any of the organs tested. The data demonstrate that MK regulates Ptn gene expression with a high degree of organ specificity, suggesting that Ptn gene expression follows Mk gene expression in development, that the increase in Ptn gene expression is compensatory for the absence of MK in Mk -/- mice, that PTN and MK share a high degree of functional redundancy, and that MK may be very important in the development of heart in mouse.

Animals↗
PubMed1997

Multiple sclerosis: re-expression of a developmental gene in chronic lesions correlates with remyelination.

Central nervous system tissue from multiple sclerosis and non-multiple sclerosis subjects was studied for the expression of exon 2 myelin basic protein gene products at the protein and message levels by immunocytochemistry and in situ hybridization, respectively. The exon 2-encoded protein sequence is normally expressed during development (myelination) within the 21.5- and 20.2-kd isoforms of myelin basic protein and is downregulated in the adult central nervous system where the 18.5- and 17.2-kd isoforms predominate, the latter devoid of exon 2 owing to alternative splicing. Exon 2 myelin basic protein gene products were readily demonstrable in multiple sclerosis samples, the highest levels correlating with remyelination in chronic lesions while normal adult central nervous system and non-multiple sclerosis material showed very low levels and fetal human central nervous system tissue (a positive control) showed high levels. We conclude that recapitulation of ontogenetic events during myelin repair accounts for the increased expression of the exon 2-encoded protein sequence in the adult central nervous system during multiple sclerosis, an event that might underly the previously observed T-cell activation to this protein sequence during relapses.

Acute Disease↗
PubMed2000

Fetal lung development: airway pressure enhances the expression of developmental genes.

BACKGROUND/PURPOSE: The mechanisms by which static airway pressures in the developing lung affect development are unknown. The in vitro murine fetal lung model with airway ligation reproduces the phenomenon of intraluminal airway pressure in developing lungs. We have applied the technique of differential display of mRNAs to fetal murine lungs that were maintained in organ culture with and without tracheal ligation. The goal of this investigation was to identify genes that are induced or enhanced by airway pressure during lung development. METHODS: Fetuses were harvested from CD-1 mice on gestational day (Gd) 14. The lungs were removed and trachea either transected or ligated and organ cultured for 7 days. Total RNA was extracted from cultured unligated controls and ligated lungs. Reverse transcription (RT) of the purified total RNA from each pooled sample was performed with anchor primer H-T11G or C and one of 24 arbitrary primers followed by polymerase chain reaction (PCR) of the RT mixtures. PCR products were electrophoresed on a DNA sequencing gel. Differentially expressed cDNA bands of interest were cut from the dried gel. Each cDNA was then reamplified. Reamplified cDNAs were extracted, PCR amplified, cloned, and sequenced for homology to existing sequences in the GenBank database. RESULTS: Sequencing identified 4 differentially expressed genes enhanced by tracheal ligation: hepatoma-derived growth factor (HDGF), ribosomal protein S24, stathmin, and parathyroid hormone (PTH). CONCLUSIONS: Genes enhanced by airway pressure or tracheal ligation are mitogenic for fibroblasts, correlate with cell proliferation, regulate cell proliferation and differentiation, and may play a role in growth in distal lung and type II cell differentiation. Further work is necessary to identify the mechanisms by which these genes influence lung maturational processes.

Aniline Compounds↗
PubMedDate not supplied

The Drosophila developmental gene snail encodes a protein with nucleic acid binding fingers.

Pattern formation in the Drosophila embryo requires the concerted expression of maternal and zygotic genes. At least nineteen genes, twelve of which are maternally expressed, are involved in the establishment of dorsal-ventral polarity. Mutations in any one of these genes result in distinct alterations of cell fates and in the formation of an abnormal dorsal-ventral pattern. Mutants of the 'dorsal group', eleven of the maternal genes, have a common recessive phenotype similar to that described for dorsal, in that cells located at ventral and lateral positions assume dorsal fates and ventral structures fail to develop. Thus the dorsal group gene products may be involved in the establishment of a gradient of positional information along the dorsal-ventral axis. We have cloned snail (sna), a zygotic gene, whose expression is essential for the correct specification of dorsal-ventral pattern. In this report, we present evidence that the complementary DNA-deduced protein product of sna contains five copies of a nucleic acid-binding finger motif previously identified in two transcription factors, and in the protein product of several putative regulatory genes.

Amino Acid Sequence↗
PubMed1988

Two developmental genes encoding sigma factor homologs are arranged in tandem in Bacillus subtilis.

The sporulation-essential gene spoIIG of the Gram-positive bacterium Bacillus subtilis encodes the sporulation-specific sigma factor sigma 29(sigma E). We report here the initial characterization of a gene, referred to as ORF3, located immediately downstream of the spoIIG gene. The results indicate that ORF3 encodes a sigma homolog, whose expression is highly regulated during development. Analysis of the ORF3 nucleotide sequence reveals an open reading frame encoding a polypeptide of 260 amino acid residues (molecular mass of 30.1 kDa). Its predicted amino acid sequence shows significant similarity to that of other RNA polymerase sigma factor sequences. S1 nuclease mapping experiments indicate that ORF3 is initially cotranscribed with spoIIG from about 1 to 4 hr into the sporulation process and that later on ORF3 is transcribed independently from a new site located between spoIIG and ORF3. The role of ORF3 was investigated by constructing a deletion mutation in its structural gene. The mutant exhibits normal growth but is unable to produce heat-resistant spores. We propose that the ORF3 gene product is a sigma factor or a related peptide essential for sporulation at a late stage of development.

Amino Acid Sequence↗
PubMed2003

The product of a developmental gene, crgA, that coordinates reproductive growth in Streptomyces belongs to a novel family of small actinomycete-specific proteins.

On solid media, the reproductive growth of Streptomyces involves antibiotic biosynthesis coincident with the erection of filamentous aerial hyphae. Following cessation of growth of an aerial hypha, multiple septation occurs at the tip to form a chain of unigenomic spores. A gene, crgA, that coordinates several aspects of this reproductive growth is described. The gene product is representative of a well-conserved family of small actinomycete proteins with two C-terminal hydrophobic-potential membrane-spanning segments. In Streptomyces avermitilis, crgA is required for sporulation, and inactivation of the gene abolished most sporulation septation in aerial hyphae. Disruption of the orthologous gene in Streptomyces coelicolor indicates that whereas CrgA is not essential for sporulation in this species, during growth on glucose-containing media, it influences the timing of the onset of reproductive growth, with precocious erection of aerial hyphae and antibiotic production by the mutant. Moreover, CrgA subsequently acts to inhibit sporulation septation prior to growth arrest of aerial hyphae. Overexpression of CrgA in S. coelicolor, uncoupling any nutritional and growth phase-dependent regulation, results in growth of nonseptated aerial hyphae on all media tested, consistent with a role for the protein in inhibiting sporulation septation.

Actinobacteria↗
PubMed2005

[The effect of protein kinase C alpha on expression of developmental genes during differentiation of mouse embryonic stem cells into neuron-like cells in vitro].

OBJECTIVE: To study the effect of protein kinase C alpha on the expression of developmental genes pax-6, slit-2 and netrin-1 during differentiation of mouse embryonic stem cells into neuron-like cells in vitro, in an attempt to elucidate their roles in signaling. METHODS: ES-BALB/c cells were induced to form embryoid bodies in the ES conditioned medium for 4 days, and were plated separately on coated glass coverslip into 6-well culture dishes for immunohistochemical study and into 100 mm dishes for RT-PCR assay. These cultures were collected after 1, 3, 5, 7 and 14 days in the presence of 5 x 10(-7) mol/L retinoic acid (RA). The neuron-like cells were stained with antibody to NSE and NF-200. mRNA level of the development related genes (pax-6, slit-2 and netrin-1) in undifferentiated and differentiated ES cells was assessed by RT-PCR assay. Effects of PMA and D-sphingosine on the developmental genes were also observed. RESULTS: Most of the neuron-like cells stained with the antibodies to NSE and NF-200. RT-PCR assay showed that levels of PKC alpha, pax-6 and netrin-1, but not slit-2 transcripts decreased dramatically upon induction on the 1st day, but then raised slowly and resumed to normal level on 14th day. PMA upregulated the levels of PKC alpha, pax-6 and netrin-1; while D-sphingosine downregulated their levels. CONCLUSIONS: The results of the present experiments demonstrate that the developmental genes pax-6 and netrin-1 play a very important role during differentiation of mouse ES cells into neuron-like cells through PKC alpha signaling pathway.

Animals↗
PubMed1997

[Developmental genes and dysmorphology].

Until recently, clinical dysmorphology was the poor parent of clinical medicine and human genetics. However, the studies of children affected with multiple congenital abnormality syndromes are the first step to recognize syndromes for diagnosis identification, leading to prognosis and care for the children and to genetic counseling for the family. These studies must lead to the identification and analysis of developmental genes involved in normal and abnormal morphogenesis. Dysmorphology leads to a better understanding of abnormal development, genetic causes and embryological development. The identification of different genes from various gene families involved in dysmorphogenesis has recently emerged. These developmental genes often act as patterning genes and as possible oncogenes; they are of interest for developmental biologists and for medical geneticists.

Abnormalities, Multiple↗
PubMed2002

Polymorphism patterns in two tightly linked developmental genes, Idgf1 and Idgf3, of Drosophila melanogaster.

A new developmental gene family, recently identified in D. melanogaster, has been called imaginal disc growth factors (IDGF) because the proteins promote growth of cell lineages derived from imaginal discs. These are the first genes reported that encode polypeptide factors with mitotic activity in invertebrates. Characteristics such as similar arrangement of introns and exons, small size, and different cytological localization make this family an excellent candidate for evolutionary studies. We focus on the loci Idgf1 and Idgf3, two genes that possess the most distinctive features. We examine the pattern of intra- and interspecific nucleotide variation in the sequences from 20 isogenic lines of D. melanogaster and sequences from D. simulans and D. yakuba. While MK, HKA, and Tajima's tests of neutrality fail to reject a neutral model of molecular evolution, Fu and Li's test with outgroup and McDonald's test suggest that balancing selection is modulating the evolution of the Idgf1 locus. The rate of recombination between the two loci is high enough to uncouple any linkage disequilibrium arising between Idgf1 and Idgf3, despite their close physical proximity.

Animals↗
PubMed2001

[Developmental genes and heart disease].

The past three years can be considered in cardiology as critical for understanding the relevance of developmental genes in the adult cardiac physiology. Also, for the first time, endogenous control of programmed cell death has been demonstrated to mark the transition between normal adaptation and cardiac hypertrophy. Most of this work has been based on previous analysis using molecular markers of cardiac determination and differentiation, work that has served a double aim: First, the determination of the cellular process that contribute to the specification of the working heart and secondly, the characterization of key regulatory factors in cardiogenesis. These studies in conjunction with the recent availability of single gene mutation in transgenic mice have furnished a new perspective in the nature of cardiac defects either in shape or function. Here we review some of the key factors in cardiac morphogenesis from the perspective of the analysis of gene mutation.

Genes↗
PubMed1994

HLA: fertile territory for developmental genes?

The HLA gene complex is well known for several reasons, for example, for immunologic studies of peptide presentation, the remarkable polymorphism and the ensuing problems in transplantation, and the association of particular alleles and haplotypes with susceptibility to autoimmune and inflammatory diseases. But for nearly 20 years, there have also been sporadic reports of HLA associations with neural tube defects, spontaneous abortion and infertility, and observations of transmission distortion and deficits of homozygotes. Part of the interest in these reports is because of the identification of developmental genes in or near the murine MHC that affect embryonic and germ cell differentiation. The first part of this review discusses current gene mapping of murine chromosome 17 and human chromosome 6, in light of the spectrum of new genes that have been identified and the colinearity of genes in the two MHCs. The second part scrutinizes published data on HLA associations.

Animals↗
PubMed1995

Clinical dysmorphology beyond developmental genetics: recent advances in some human developmental genes.

Dysmorphology is involved in abnormal development, genetic causes and embryological development. The clinical studies of dysmorphic syndromes must lead to the identification and analysis of developmental genes involved in normal and abnormal morphogenesis. The identification of different genes from various gene families involved in dysmorphogenesis has recently emerged. The authors review the recent advances in some human developmental gene families (PAX, FGFR, BMP genes). These genes often act as patterning genes and as possible oncogenes; they are of interest for developmental biologists and for medical geneticists.

Animals↗
PubMed2001

A Dictyostelium nuclear phosphatidylinositol phosphate kinase required for developmental gene expression.

The generation of diacylglycerol (DAG) in response to receptor stimulation is a well-documented signalling mechanism that leads to activation of protein kinase C (PKC). Putative alternative effectors contain sequences that interact with DAGs, but the mechanisms of signal transduction are unknown. We have identified a Dictyostelium gene encoding a novel protein which contains a domain with high identity to the DAG-binding domain of PKC. It does not encode a PKC homologue as the conservation does not extend outside this region. We confirm that the proposed DAG-binding domain is sufficient to mediate interaction of a fusion protein with vesicles containing DAG. The protein also shows significant homology to mammalian phosphatidylinositol phosphate (PIP) kinases and we show that this domain has PIP kinase activity. The protein, PIPkinA, is enriched in the nucleus and abrogation of gene function by homologous recombination inhibits early developmental gene expression, blocking development at an early stage. Thus, we have identified a PIP kinase from Dictyostelium which is required for development, is a candidate effector for DAG and has the potential to synthesize nuclear PIP(2).

Animals↗