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PubMed2000

Abnormalities of somite development in the absence of retinoic acid.

We describe the effects of an absence of retinoic acid (RA) on the development of somites in the quail embryo. RA was removed by generating vitamin A deficient quail embryos whereupon the resulting defects in the embryos can be analysed. The effect on the somites is threefold. Firstly, they are half the size of normal, but the total number of somites is the same as normal. There has therefore been some global regulation event. Secondly, by TUNEL staining and TEM we show that the lateral halves of all of the somites undergo apoptosis between stages 11 and 14. This effect is confined to the sclerotome of the somites. Thirdly, some of the genes involved in somite differentiation are down-regulated such as fgf-4, fgf-8, engrailed and myogenin whereas others we examined such as cek-8, Delta, follistatin and myf5 are not affected. These studies reveal remarkably specific effects of RA on developmental gene pathways in the embryo.

Animals↗
PubMed1993

Osteocalcin gene promoter-binding factors are tissue-specific nuclear matrix components.

The nuclear matrix appears to play an important role in developmental gene expression during osteoblast differentiation. To better understand this role, we examined nuclear matrix DNA-binding proteins that are sequence-specific and interact with the osteocalcin gene promoter. Multiple protein-DNA interactions involving two distinct nuclear matrix proteins occur within the 5' regulatory sequences (nt -640 to -430). One of these proteins, NMP-1, is a ubiquitous, cell growth-regulated protein that is related to the transcription factor ATF and resides in both the nuclear matrix and the nonmatrix nuclear compartment. The other protein, NMP-2, is a cell type-specific, 38-kDa promoter factor that recognizes binding sites resembling the consensus site for the CCAAT/enhancer-binding protein C/EBP and is localized exclusively on the nuclear matrix. NMP-1 and NMP-2 each interact with two nuclear matrix protein-binding elements. These elements are present near key regulatory sites of the osteocalcin gene promoter, such as the principal steroid hormone (vitamin D)-responsive sequences. Binding in this region of the osteocalcin gene promoter suggests transient associations with the nuclear matrix that are distinct from the stable interactions of matrix attachment regions. Our results are consistent with involvement of the nuclear matrix in concentrating and/or localizing transcription factors that mediate the basal and steroid hormone responsiveness of osteocalcin gene transcription.

Animals↗
PubMed2004

NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reduction defects. We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLS and determined its structure and the structures of mouse, rat and zebrafish homologs. We named its protein product delangin. Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B. We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS. Genome analyses typically identify individual delangin or Nipped-B-like orthologs in diploid animal and plant genomes. The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggests that there are parallels between CdLS and Roberts syndrome.

Animals↗
PubMed2004

Sequence and expression of the rainbow trout winged helix/forkhead transcription factor FoxF1.

FoxF1 is a member of the winged helix/forkhead transcription factor gene family. We have cloned the cDNA encoding a rainbow trout FoxF1 homologue, and examined its developmental gene expression pattern. By 7 days postfertilization (dpf at 14 degrees C), FoxF1 is expressed throughout the alimentary tract in the mesenchymal cells adjacent to the endodermal epithelium, with intense signals on the dorsal side of the oral cavity and in the primitive stomach. As ontogeny proceeds, expression is down-regulated in the oral cavity and esophagus, but persists in the pharynx, stomach, and intestine. Hybridization signals are also detected in the developing liver, and in the mesenchyme layer around the notochord. From 18dpf onwards, dramatic changes occur in gene expression in the branchial region. As the gill filaments elongate from the branchial arches, FoxF1 begins to be expressed along the central cell cord running through each gill filament, and then switches over its rod-like expression to a repetitive pattern, alternating on either side along the proximal part of the filament. A signal is further localized to the primitive pillar cells as they form gill lamellae. In addition to illustrating the conserved FoxF1 expression pattern in the developing digestive tract and liver, the results indicate a close association of FoxF1 with the formation of the fish gills.

Amino Acid Sequence↗
PubMed2005

Stage-specific induction of DNA methyltransferases in olfactory receptor neuron development.

DNA methylation-dependent gene silencing, mediated by DNA methyltransferases (DNMTs), is essential for normal mammalian development and its dysregulation has been implicated in neurodevelopmental disorders. Despite this, little is known about DNMTs in the developing or mature nervous system. Here, we show that DNMT1, 3a and 3b are expressed at discrete developmental stages in the olfactory neuron lineage, coincident with key shifts in developmental gene expression. DNMT1 is induced in cycling progenitors and is retained in post-mitotic olfactory receptor neurons (ORNs). DNMT3b is restricted to mitotic olfactory progenitors, whereas DNMT3a is expressed only in post-mitotic immature neurons prior to ORN terminal maturation, coincident with histone deacetylase 2 (HDAC2), a key downstream effector of methylation-dependent chromatin condensation. Similar stage-specific expression of DNMT3b and 3a was also found in other developing sensory and CNS neurons. This suggests that progressive lineage restriction regulated by methylation-dependent silencing could be a highly conserved mechanism shared by multiple lineages in the developing nervous system.

Animals↗
PubMed1997

A molecular strategy designed for the rapid screening of gene traps based on sequence identity and gene expression pattern in adult mice.

We have devised a strategy to rapidly screen gene traps in mouse embryonic stem (ES) cells based on DNA sequence information and an in vitro analysis of gene expression. After the initial identification of ES cell clones expressing beta-galactosidase, tagged RNA transcripts were immediately cloned and sequenced in order to determine their identities. Novel gene sequences found were used to probe northern blots to examine the expression patterns of their cognate genes. Our initial characterization of 30 cDNA clones indicated that more than half of the tagged sequences were novel mouse genes and of these 40% showed a restricted pattern of expression in adult mouse tissues. This molecular characterization of gene traps is quick, reliable and well suited for the large-scale screening of mammalian developmental genes. Furthermore, since gene trap insertion frequently disrupts the tagged host gene, the ES cells can be used to produce transgenic animals for a genetic analysis of gene function.

Animals↗
PubMed1999

A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3.

In spondylocostal dysostosis (SD), vertebral-segmentation defects are associated with rib anomalies. This results in short-trunk short stature, nonprogressive kyphoscoliosis, and radiological features of multiple hemivertebrae and rib fusions. SD can be familial, and both autosomal dominant and autosomal recessive (AR) inheritance have been reported, but no genes have been identified or localized for nonsyndromic SD in humans. We performed genomewide scanning by homozygosity mapping in a large consanguineous ARSD Arab Israeli family with six definitely affected members. Significant linkage was found to chromosome 19q13, with a LOD score of 6.9. This was confirmed in a second Pakistani family with three affected members, with a LOD score of 2.4. The combined-haplotype data identify a critical region between D19S570 and D19S908, an interval of 8.5 cM on 19q13.1-19q13.3. This is the first study to localize a gene for nonsyndromic SD. ARSD is clinically heterogeneous and is likely to result from mutations in developmental genes or from regulating transcription factors. Identification of these genes will improve the understanding of the molecular processes contributing to both normal and abnormal human vertebral development.

Adolescent↗
PubMed2026

Evolutionary conservation of heat shock proteins in Blattodea and their roles in wing morphogenesis and ovarian development of Blattella germanica.

Heat shock proteins (Hsps) are essential molecular chaperones for protein homeostasis and stress responses. However, the Hsp repertoires and functions in Blattodea remain underexplored. Our genome-scale survey of nine Blattodea species revealed 37-46 conserved Hsp90, Hsp70, and DNAJ (Hsp40) genes, with DNAJ the most abundant and Hsp90 the least. Phylogenetic analysis confirmed the evolutionary conservation of three Hsp90, seven Hsp70, and 29 DNAJ subclades in Blattodea. Selection pressure analysis revealed predominant purifying selection (dN/dS ≪ 1) across lineages, strongest in DNAJ and highest in Hsp90 conservation. In Blattella germanica, expression of six representative BgHsp genes progressively increased during development, peaking in fifth-instar nymphs. Tissue expression profiling revealed that BgHspA1-2/3/4 were predominantly expressed in legs, BgDNAJB5 and BgHsp90AB1-2 were enriched in the fat body, and BgHsp90AB1 was highly expressed in the head. dsRNA injection targeting conserved Hsp gene regions achieved 61.9-94.1% knockdown of all six target genes. RNAi knockdown of six BgHsp genes disrupted wing morphogenesis, causing distinct phenotypes: wing whitening (56.7%, dsBgHspA1-4), unequal length (66.7%, dsBgHspA1-3; 76.7%, dsBgDNAJB5), and wing wrinkling (70%, dsBgHspA1-2; 63.3%, dsBgHsp90AB1; 76.7%, dsBgHsp90AB1-2). During ovarian formation, the developmental delay was most severe in the dsBgHsp90AB1 group, moderate in the dsBgHsp90AB1-2 and dsBgHspA1-2/3/4 groups, and weakest in the dsBgDNAJB5 group. Besides, knockdown significantly downregulated key developmental genes (apterous-a, nubbin, scalloped, ultrabithorax, wingless, and vitellogenin). These findings provide a reference for understanding the evolutionary patterns of Hsps in Blattodea, and offer mechanistic insights into the developmental regulation mediated by Hsps in this important public-health pest.

Animals↗
PubMed2003

Statistical extraction of Drosophila cis-regulatory modules using exhaustive assessment of local word frequency.

BACKGROUND: Transcription regulatory regions in higher eukaryotes are often represented by cis-regulatory modules (CRM) and are responsible for the formation of specific spatial and temporal gene expression patterns. These extended, approximately 1 KB, regions are found far from coding sequences and cannot be extracted from genome on the basis of their relative position to the coding regions. RESULTS: To explore the feasibility of CRM extraction from a genome, we generated an original training set, containing annotated sequence data for most of the known developmental CRMs from Drosophila. Based on this set of experimental data, we developed a strategy for statistical extraction of cis-regulatory modules from the genome, using exhaustive analysis of local word frequency (LWF). To assess the performance of our analysis, we measured the correlation between predictions generated by the LWF algorithm and the distribution of conserved non-coding regions in a number of Drosophila developmental genes. CONCLUSIONS: In most of the cases tested, we observed high correlation (up to 0.6-0.8, measured on the entire gene locus) between the two independent techniques. We discuss computational strategies available for extraction of Drosophila CRMs and possible extensions of these methods.

Animals↗
PubMed2005

The future of pediatric nephrology.

The delineation of renal disease in children dates to the 1880s with descriptions of Henoch's purpura, bladder exstrophy, renal rickets and nephritis. The discipline of pediatric nephrology mainly emerged during the 20th century in response to problems in fluid and electrolyte balance, characterization of the nephrotic syndrome, use of renal biopsy, antibiotic therapy of urinary tract infections, dialysis and transplantation in children, growth problems associated with chronic renal failure, detection and therapy of hypertension, and the creation of both national and international pediatric nephrology societies and a journal now in its 18th year. The development of molecular and cell biology, genetic and genomic techniques and bioinformatics methods underlie many future directions. We should anticipate further elucidation of single gene disorders, of complex trait analysis of disorders, such as diabetic nephropathy and hypertension, the interplay of developmental genes and gene products and interactions within the podocyte. Specific therapies directed against inflammation, vascular damage, cyst development, the ravages of proteinuria and graft rejection (or induction leading to tolerance) will be developed. Stem cell therapies may replace lost renal mass, even of specific nephron sites. Novel therapies will also modulate the cell cycle, tyrosine kinase signaling and apoptosis. In addition, drugs will be specifically tested in children for many renal conditions. Larger and more specialized registries will be developed; epidemiologic studies and exploration of large data sets will lead to clinical guidelines that are evidenced-based. There is a need for more careful measurement of glomerular filtration rate (GFR), proteinuria and cytokines, and a fuller appreciation of the nutritional and hormonal role of the kidney. Finally, the antecedents of adult renal disease and the need to intervene in a proactive fashion will be realized. Despite these impressive advances in care, the greatest challenges will be in providing children with renal disease access to well-trained pediatric nephrologists, especially in Asia (1 billion children), Africa, Central and South America, and in immigrant and refugee populations. Included in this challenge is the capacity to have affordable access to use of contemporary techniques, and effective medications and prevention strategies. The International Pediatric Nephrology Association (IPNA), its journal, and pediatric advocates will need to use their energies to take on these challenges.

Child↗
PubMed2006

The secretory ependymal cells of the subcommissural organ: which role in hydrocephalus?

Ependyma in the central nervous system gives rise to several specialized cell types, including the secretory ependymal cells located in the subcommissural organ. These elongated cells show large cisternae in their cytoplasm, which are filled with material secreted into the cerebrospinal fluid and toward the leptomeningeal spaces. A specific secretion of the subcommissural organ was named SCO-spondin, regarding its marked homology with developmental proteins of the thrombospondin superfamily (presence of thrombospondin type 1 repeats). The ependymal cells of the subcommissural organ and SCO-spondin secretion are suspected to play a crucial role in cerebrospinal fluid flow and/or homeostasis. There is a close correlation between absence of the subcommissural organ and hydrocephalus in rat and mouse strains exhibiting congenital hydrocephalus, and in a number of mice transgenic for developmental genes. The ependymal cells of the subcommissural organ are under research as a key factor in several developmental processes of the central nervous system.

Animals↗
PubMed2000

amiB, a novel gene required for the growth/differentiation transition in Dictyostelium.

BACKGROUND: The differentiation programme of Dictyostelium discoideum is initiated by starvation. Nutrient depletion triggers the differentiation of Dictyostelium cells through the transcriptional inactivation of some growth-phase genes, as well as through the transcriptional activation of essential genes required for the aggregation of the cells. The adenylyl cyclase (ACA) gene, acaA, is one of the earliest genes expressed following starvation. ACA produces intracellular and extracellular cAMP that drives further differentiation by inducing chemotaxis, developmental gene expression and morphogenesis of Dictyostelium cells. Although several genes have been identified as being essential for the initiation of differentiation process, such as the transcriptional activation of ACA expression, the molecular mechanisms of the growth/differentiation transition remain to be explored. RESULTS: Using insertional mutagenesis, we have isolated a mutant that does not aggregate upon starvation. The disrupted gene, amiB (aggregation minus B), is predicted to encode a novel protein of 298.9 kDa. When starved, amiB- cells produced an undetectable level of cAMP. Analyses of gene expression showed that amiB- cells fail to turn off the expression of one of the growth-phase genes, cprD, and to turn on the expression of ACA following starvation. The ectopic expression of ACA from a constitutive promoter rescued the differentiation and morphogenesis of amiB- mutants. Furthermore, the ectopic expression of a putative transcriptional factor DdMyb2 or a catalytic subunit of cAMP-dependent protein kinase (PKA-C), both of which are thought to be involved in ACA expression pathway(s), also rescued the starvation-induced ACA expression and further differentiation of the amiB- mutant. CONCLUSION: These results suggest that AmiB plays a role at the start of Dictyostelium differentiation through induction of the ACA expression which is essential for cAMP signalling.

Adenylyl Cyclases↗
PubMed1991

Biological hierarchies and the concept of homology.

Although most biologists agree that homology must be defined in terms of common ancestry, the details of this definition remain controversial. We review briefly the disagreements concerning the formal definition of homology and the methodology used to establish specific cases of homology. Our principal focus, however, is a third area of disagreement: whether morphological characters can be homologous even if their developmental and genetic bases are not homologous, and whether behavioral characters can be homologous even if their morphological substrates are not homologous. We contend that attempts to reduce behavioral homology to morphological homologies, and morphological homology to genetic and developmental homologies, are misguided and based on a failure to recognize the hierarchical nature of biological organization. Genes, developmental processes, morphological structures, physiological functions and behaviors all constitute different levels of biological organization. These levels are causally interrelated, but there is no one-to-one correspondence between characters at different levels. Furthermore, the causal relationships between characters at different levels may change during the course of evolution. As a result, higher level characters may be homologous, even though some of their constituent lower level characters are not homologous. In support of this assertion, we provide several examples of homologous morphological characters that are based on non-homologous developmental precursors and processes, and of homologous behavioral characters that are based on non-homologous morphological structures. In allowing one to recognize homologies at any level of organization, independently of homologies at other levels, the hierarchical concept of homology also allows one to ask important questions about how evolutionary changes at the various levels of organization are related to one another.

Animal Communication↗
PubMed1998

Changes in the pattern of twisted gastrulation gene expression among Drosophila species.

A long-standing hypothesis posits that morphological changes may be more likely to result from changes in regulation of gene expression than from changes in the protein coding sequences of genes. We have compared the expression pattern of the twisted gastrulation (tsg) gene among five Drosophila species: D. melanogaster, D. simulans, D. subobscura, D. mojavensis, and D. virilis. The tsg gene encodes a secreted protein that is required for the specification of dorsal midline fates in the Drosophila early embryo. TSG is unlike other secreted growth and differentiation factors in Drosophila in that its expression pattern can be experimentally varied and still result in normal development. Because of this, its regulatory region may be freer to diverge than that of other developmental genes whose misexpression may lead to lethal defects. Thus, the tsg gene may be a good indicator of the frequency and nature of evolutionary changes affecting patterns of gene expression. Over approximately 60 million years (Myr), the tsg gene has retained a dorsal-on/ventral-off pattern and a middorsal region of expression; but there have been marked changes in the middorsal domain of expression as well as the appearance/loss of other domains of expression along the anterior/posterior axis. Changes between closely related species (approximately 2-5 Myr since divergence) that are not reflected among more distantly related species suggest frequent changes in gene expression over evolutionary time. These changes in gene expression may serve as the raw material for eventual evolutionary changes in morphology.

Animals↗
PubMedDate not supplied

Retinoic acid induces a tissue-specific deletion in the expression domain of Otx2.

The expression domain of Otx2, a gene essential for the development of the fore- and midbrain, has previously been shown to be affected by exposure to all-trans-retinoic acid (AT-RA). However, morphological abnormalities of the fore- and midbrain induced by exposure of early somite-stage embryos to AT-RA were not associated with abnormal Otx2 expression. To identify abnormal expression of developmental genes induced by exposure at early somite-stages, we performed a fine analysis of the expression domains of Otx2, Otx1, Emx2, and Pax-6 by combining in situ hybridization (ISH) with computer-assisted superpositions and three-dimensional reconstructions of these expression domains. No alteration in the relative location of the caudal boundaries of the expression domains of these genes was observed. The only abnormality was a deletion of the most cranial portion of the neural folds (NF).

Animals↗
PubMed1998

The role of PAX2 in normal and abnormal development of the urinary tract.

The molecular etiology of many urinary tract abnormalities in children remains unknown, but a number of genes with a key role in urogenital development have now been identified. PAX2, one such gene, encodes a transcription factor which is critically required for epithelial differentiation within the urogenital tract. Recent studies suggest that PAX2 mutations lead to urological abnormalities and renal failure, while overexpression of PAX2 in the kidneys of mice causes multifocal microcystic tubular dilatation. In humans persistent PAX2 expression has been identified in multicystic dysplastic kidneys. In this review, recent research on the developmental gene, PAX2, and its involvement in normal and abnormal kidney development is summarized. In addition, an overview of the phenotypes associated with either loss-of-function PAX2 mutations or PAX2 overexpression is presented. A brief summary of factors that are known to regulate PAX2 and genes that may be regulated by PAX2 protein is also included.

Animals↗
PubMed1995

PAX-genes expression during human embryonic development, a preliminary report.

PAX-genes encode important transcriptional factors during embryogenesis. They are also involved in human diseases, Waardenburg syndrome, Aniridia and tumors. We report in the present paper a preliminary in situ hybridization study of PAX3-, PAX5- and PAX6-gene expression during human embryonic development. PAX3-gene is expressed in the neural groove before closure, and in the closed neural tube. Afterwards, its expression is observed in the mesencephalon, the rhombencephalon and the spinal cord. PAX5-gene expression is restricted to the mesencephalon-rhombencephalon boundary and the spinal cord. PAX6-gene is expressed early in the neural tube, just after its closure. Afterwards, its expression is observed in the forebrain, the rhombencephalon, the somites and the spinal cord. These patterns of expression are observed early during human embryonic development and are specific in time and space. This preliminary report shows the feasibility of in situ hybridization methodology for studying the expression of developmental genes during the early stages of human embryogenesis. It opens the way to study the pathogenesis of polymalformative syndromes and tumorigenesis.

Chromosome Mapping↗
PubMed2000

Midkine is expressed early in rat fetal adrenal development.

Adrenal gland development is complex and poorly understood at the molecular level. Only a subset of patients with adrenal hypoplasia congenita (AHC) carry mutations in DAX1, a member of the nuclear hormone receptor superfamily. Therefore we set out to identify other candidate genes responsible for AHC by characterizing genes involved in fetal adrenal development. To identify these genes, we studied the differential expression of genes in fetal rat adrenals comparing tissues at 14 and 15 days postcoitum (dpc) since this period encompasses major morphological change in rat adrenal development. Fetal rat adrenals were dissected, cDNAs were prepared, and suppressive subtractive hybridization was performed. We isolated 126 clones of putatively differentially expressed clones and approximately 250 bp of each of the clones was sequenced. The most interesting putative developmental genes were examined. One member of the extracellular PTN/MDK (pleiotrophin/midkine) heparin-binding protein family involved in regulation of growth and differentiation was selected for initial study. We obtained full-length transcript by 3' rapid amplification of cDNA ends and performed Northern analysis on rat adrenal RNA from fetuses at 13, 14, 15, 17, and 19 dpc and newborns. Results from those analyses demonstrated the highest Mdk expression at days 13 and 14 followed by a moderate decrease of expression during the fetal stages thereafter. In the newborn, Mdk expression is nearly undetectable. Our results indicate that Mdk has a very specific pattern of fetal expression in the adrenals. We conclude that Mdk is involved early in fetal development of the rat adrenal. Therefore, MDK is a candidate gene for AHC not due to DAX1 mutations.

Adrenal Glands↗