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PubMed2004

Death and more: DNA damage response pathways in the nematode C. elegans.

Genotoxic stress is a threat to our cells' genome integrity. Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale genomic instability. Because such changes may have tumorigenic potential, damaged cells are often eliminated via apoptosis. Loss of this apoptotic response is actually one of the hallmarks of cancer. Towards the effort to elucidate the DNA damage-induced signaling steps leading to these biological events, an easily accessible model system is required, where the acquired knowledge can reveal the mechanisms underlying more complex organisms. Accumulating evidence coming from studies in Caenorhabditis elegans point to its usefulness as such. In the worm's germline, DNA damage can induce both cell cycle arrest and apoptosis, two responses that are spatially separated. The latter is a tightly controlled process that is genetically indistinguishable from developmental programmed cell death. Upstream of the central death machinery, components of the DNA damage signaling cascade lie and act either as sensors of the lesion or as transducers of the initial signal detected. This review summarizes the findings of several studies that specify the elements of the DNA damage-induced responses, as components of the cell cycle control machinery, the repairing process or the apoptotic outcome. The validity of C. elegans as a tool to further dissect the complex signaling network of these responses and the high potential for it to reveal important links to cancer and other genetic abnormalities are addressed.

Animals↗

PubMed2006

Exaggerated vasomotor response to ANG II in rats with fetal programming of hypertension associated with exposure to a low-protein diet during gestation.

The renin-angiotensin system plays a key role in the initiation and maintenance of elevated blood pressure associated with altered intrauterine milieu. The current studies were undertaken to verify whether vascular response to ANG II is increased in adult offspring of low-protein fed dams (LP) compared with control (CTRL) and if so, to examine underlying mechanism(s). ANG II-induced contraction of carotid rings was increased in LP (E(max), the maximum asymptote of the curve, relative to maximal response to KCl 80 mM: 230 +/- 3% LP vs. 201 +/- 2% CTRL, P < 0.05). In both groups, contraction to ANG II was mediated solely by AT1R. Responses to thromboxane A2 analog U-46619 and to KCl 80 mM under step increases in tension were similar between groups. Endothelium depletion enhanced contraction to ANG II in both groups, more so in LP. Blockade of endothelin formation had no effect on response to ANG II, and ANG-(1-7) did not elicit vasomotor response in either group. Superoxide dismutase (SOD) analog Tempol normalized LP without modifying CTRL response to ANG II. Basal levels of superoxide (aortic segments, lucigenin-enhanced chemiluminescence and fluorescent dye hydroethidine) were higher in LP. ANG II further increased superoxide production in LP only, and this was inhibited by coincubation with diphenylene iodonium or apocynin (inhibitor of NADPH oxidase complex). AT1R expression in carotid arteries was increased in LP, whereas SOD expression was unchanged. In conclusion, vasoconstriction to ANG II is exaggerated in this model of developmental programming of hypertension, secondary to enhanced vascular production of superoxide anion by NADPH oxidase with concomitant increase of AT1R expression.

Age Factors↗

PubMed1998

Developmental regulation of bicoid mRNA stability is mediated by the first 43 nucleotides of the 3' untranslated region.

During the transition from the maternal to the zygotic developmental program, the expression of genes important for pattern formation or cell cycle regulation changes dramatically. Rapid changes in gene expression are achieved in part through the control of mRNA stability. This report focuses on bicoid, a gene essential for formation of anterior embryonic structures in Drosophila melanogaster. bicoid mRNA is synthesized exclusively during oogenesis. Here, we show that bicoid mRNA stability is regulated. While bicoid mRNA is stable in retained oocytes, in unfertilized eggs, and during the first 2 h of embryogenesis, specific degradation is activated at cellularization of the blastoderm. To identify cis-acting sequences required for bicoid mRNA's regulated stability, fusions between bicoid and genes producing stable mRNAs were introduced into the Drosophila germ line by P-element-mediated transformation. The analysis of the fusion mRNAs identified a bicoid instability element (BIE) contained within a 43-nucleotide sequence immediately following the stop codon. The BIE is sufficient to destabilize the otherwise-stable ribosomal protein A1 mRNA and is separable from the previously identified bicoid mRNA localization signals and from the "nanos response element." Similar mechanisms may regulate a class of developmentally important maternal genes whose mRNA has a temporal profile similar to that of bicoid.

Animals↗

PubMed1991

Expression of ALZ-50 immunoreactivity in the developing principal sensory nucleus of the trigeminal nerve: effect of transecting the infraorbital nerve.

Many neurons in the CNS die as a consequence of normal development. As these neurons die, they may be programmed to produce 'death proteins'. We explored the possibility that an antigen recognized by ALZ-50, a protein expressed in Alzheimer's-type neurofibrillary tangles, is generated during the process of neuronal death. The effects of transecting the infraorbital nerve on the expression of ALZ-50 immunoreactivity and neuronal death in the principal sensory nucleus of the trigeminal nerve (PSN) was examined. In normal rats, a small number of PSN neurons was ALZ-50-positive on postnatal day (P) 3. Transections on the day of birth (i.e. during the period of naturally occurring neuronal death) led to a 5-fold increase in the number of immunoreactive neurons expressing a 56-kDa protein on P3. In contrast, lesions on P25 (i.e. after the period of naturally occurring neuronal death) did not induce any neurons to exhibit ALZ-50 immunoreactivity. Thus, the 56-kDa protein recognized by ALZ-50 appears to be a death protein which is transiently expressed during the period of naturally occurring neuronal death. It is appealing to speculate that the pathological degeneration described in Alzheimer's brains results from the up-regulation of a quiescent developmental program.

Animals↗

PubMed1999

Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch.

In mammals, the first branchial arch (BA1) develops into a number of craniofacial skeletal elements including the jaws and teeth. Outgrowth and patterning of BA1 during early embryogenesis is thought to be controlled by signals from its covering ectoderm. Here we used Cre/loxP technology to inactivate the mouse Fgf8 gene in this ectoderm and have obtained genetic evidence that FGF8 has a dual function in BA1: it promotes mesenchymal cell survival and induces a developmental program required for BA1 morphogenesis. Newborn mutants lack most BA1-derived structures except those that develop from the distal-most region of BA1, including lower incisors. The data suggest that the BA1 primordium is specified into a large proximal region that is controlled by FGF8, and a small distal region that depends on other signaling molecules for its outgrowth and patterning. Because the mutant mice resemble humans with first arch syndromes that include agnathia, our results raise the possibility that some of these syndromes are caused by mutations that affect FGF8 signaling in BA1 ectoderm.

Animals↗

PubMed2001

Eye stalks or no eye stalks: a structural comparison of pupal development in the stalk-eyed fly Cyrtodiopsis and in Drosophila.

After emergence from the puparium, stalk-eyed flies of the family Diopsidae rapidly expand their head capsule so that the eyes and optic lobes are displaced at the ends of stalks that extend from the central head. Because the expansion takes place in only 15 minutes, we are especially interested in ontogenetic modifications that may facilitate such a rapid and dramatic change. To examine the pupal development of the brain, we used Bodian staining in the stalk-eyed fly, Cyrtodiopsis whitei and compared it with development in the fruit fly, Drosophila melanogaster, which serves as a "typical" dipteran example without eye stalks. Early in pupal development, the neuropil organization of the two species is fairly similar. In both species, columns are present in the outer medulla and giant fibers are discernible in the lobula plate. In contrast to D. melanogaster, C. whitei shows a small, neck-like constriction between the optic lobes and the rest of the brain. By 20% of pupal development, the divergence is more apparent, and by 30%, the future eye stalk and optic nerve of C. whitei has started to form. During the remaining 70% of development, the initially thick optic nerve narrows, and becomes gradually elongated, eventually coiling and folding throughout the short eye stalk. Similarly, the cuticle of the surrounding region becomes constricted, slightly elongated, and gradually appears more and more densely corrugated, like an accordion bellows. However, except for the formation of the optic nerve, the dense aggregation of cuticle around it, and a shift in orientation of the neuropils, the developmental programs of the two species are remarkably similar. This suggests that only a few aspects of development have been modified during the course of evolution to generate the stalk-eyed phenotype. At eclosion, the imago of C. whitei goes through a pumping process to inflate the eye stalks to their full length. Measurements of the diameter of the optic nerve before and after the expansion reveal only a small decrease. We propose that the cuticular folding of the eye stalk as well as the coiling of the optic nerve prepare the pupa well for the rapid and dramatic eye-stalk inflation after eclosion.

Age Factors↗

PubMed1999

Murine Pkd1 is a developmentally regulated gene from morula to adulthood: role in tissue condensation and patterning.

PKD1 is the most common genetically mutated gene involved in autosomal dominant polycystic kidney disease (ADPKD). Our previous studies have shown that the pathogenesis of human and murine polycystic kidney disease (PKD) involves failure to switch out of a renal developmental program, suggesting a role for PKD1 in development. To investigate this hypothesis, we have cloned a portion of the murine Pkd1 gene and characterized the fetal to adult tissue expression pattern of Pkd1. We chose to clone the transmembrane region of Pkd1, a region prone to mutations in ADPKD. The transmembrane coding region (2.6 kb) has 80.3% nucleotide homology with human PKD1 and 85.3% amino acid similarity. The cloned murine Pkd1 fragment closely resembles that of human PKD1 with respect to both genomic size and exon/intron position. We have demonstrated that this Pkd1 region is not conserved in lower organisms and is mammalian specific. A detailed expression analysis of Pkd1 revealed expression as early as the morula stage and in ES cells with differential expression levels in various tissues/organs throughout development. Highest expression levels were observed in the early condensing mesenchyme of primitive mesoderm and ectoderm. Pkd1 was also expressed at high levels in developing neural tube, neural crest derivatives, prechondrogenic tissue, metanephros, bladder, salivary glands, lung, and blood vessels with lower expression levels in other organs and tissues. Specific spatial and temporal patterns of Pkd1 expression were demonstrated in individual organs, such as lung, kidney, brain, indicating it is highly developmentally regulated. Particularly high levels persisted in mature derivatives of neural tube, neural crest, chondrogenic tissue, metanephros, and lung. In summary, our data suggest that Pkd1 has at least two cellular functions, one a basic function involved in early tissue condensation processes, and the other a mammalian-specific function, that evolved with tissue patterning and tubulogenesis in metanephric and pulmonary development.

Animals↗

PubMed2004

The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development.

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KO brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KO neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.

Animals↗

PubMed2004

Minireview: transcriptional regulation of adrenocortical development.

The adrenal glands are comprised of two distinct endocrine organs: the outer cortex, which is derived from mesoderm and synthesizes steroid hormones, and the inner medulla, which contains neuroectodermal cells derived from the neural crest and produces the catecholamine hormones norepinephrine and epinephrine. The developmental program that gives rise to the adrenal gland begins early during embryogenesis and continues throughout gestation and well after birth. In this article, we review the molecular mechanisms of adrenal differentiation and development, focusing on the contributions of genes responsible for the development of the adrenal cortex as identified from studies of experimental animal models and human subjects with clinical diseases. These studies identify a hierarchical network of transcription factors, including Wilms' tumor-1, steroidogenic factor-1, dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked-1, PBX1, and CITED2, that both give rise to the adrenal cortex and subsequently determine its subsequent function in steroidogenesis.

Adrenal Cortex↗

PubMed2004

Physiological and sport-specific skill response of olympic youth soccer athletes.

Although many studies have been focused on soccer athletes, no comprehensive studies have been conducted on adolescent soccer athletes in the United States. Therefore, the purpose of this study was to quantify the physiological and sport-specific skill characteristics of Olympic Developmental Program (ODP) soccer athletes by age group and game experience. Following written, informed consent, 59 male athletes (age = 14.6 +/- 2.0 years; wt = 60.5 +/- 1.4 kg; ht = 172.4 +/- 1.2 cm) completed a battery of tests to determine aerobic power (VO(2)max), heart rate (HR(max)), ventilation (VE(max)), respiratory exchange ratio (RER), anaerobic threshold (AT), blood pressure (BP(rest/max)), anaerobic power/capacity [peak power (PP), mean power (MP), total work output (TWO), fatigue index (FI)], leg power [vertical squat jump (VJS), countermovement jump (VJC)], body composition [percent body fat (%BF), lean body mass (LBM)], joint range of motion (trunk, back, hip, knee, and ankle), and agility/sport-specific skills (T-test, line drill test, juggling test, Johnson wall volley, and modified-Zelenka circuit). Factor analyses with subsequent multivariate analyses of variance (MANOVAs) indicated significant main effects across age (p = 0.0001) but not by game experience (p = 0.82). Older athletes exhibited greater height, weight, LBM, VE(max), Time(max), PP, TWO, and VSJ values than younger athletes. Although not significant, there were differences with increasing age in the agility tests (T-test, wall volley, and juggling test). In conclusion, improvements in anaerobic power, agility, and sport-specific skill should be addressed at this developmental level of competition.

Adolescent↗

PubMed1992

Stochastic developmental variation in the ratio of allelic rDNAs among newly differentiated, heterozygous macronuclei of Tetrahymena thermophila.

Ciliates possess nuclear dimorphism, i.e., they carry two structurally and functionally differentiated types of nuclei. The micronucleus and macronucleus serve as the germline and somatic nuclei, respectively, of the cell. The macronucleus differentiates from a mitotic sister of the micronucleus once per life cycle. Macronuclear differentiation is accompanied by a developmentally programmed set of DNA rearrangements, including chromosome fragmentation, telomere addition, and amplification. Given the diploidy of the MAC anlage, are both homologous copies of a chromosome processed and amplified equally and simultaneously in an individual differentiating MAC? We have approached this question for the case of the rDNA, exploiting previously identified DNA polymorphisms and the sensitivity of PCR. We determined allelic ratios in individual caryonide cells, i.e., the cells carrying the primary products of MAC differentiation, prior to the first division of the newly differentiated MAC. We observed stochastic variability in allelic ratios among caryonides that start with genetically identical heterozygous MACs. Either rDNA type can be in the majority. Appropriate controls make it unlikely that the ratios observed were significantly affected by variation in the assay itself. The variability may well result from the statistical variation associated with the relative timing of individual biochemical events initiating the processing and/or amplification of a few rDNA precursor molecules, presumably 4-8 at the most, in a MAC anlage. In addition to this stochastic variability, we observed a small but distinct bias in favor of the C3 rDNA. Thus the replication advantage of C3 relative to B rDNA in heterozygous MACs, previously detected during vegetative multiplication, may begin to be expressed during developmental amplification.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed2007

Projections of Drosophila multidendritic neurons in the central nervous system: links with peripheral dendrite morphology.

Neurons establish diverse dendritic morphologies during development, and a major challenge is to understand how these distinct developmental programs might relate to, and influence, neuronal function. Drosophila dendritic arborization (da) sensory neurons display class-specific dendritic morphology with extensive coverage of the body wall. To begin to build a basis for linking dendrite structure and function in this genetic system, we analyzed da neuron axon projections in embryonic and larval stages. We found that multiple parameters of axon morphology, including dorsoventral position, midline crossing and collateral branching, correlate with dendritic morphological class. We have identified a class-specific medial-lateral layering of axons in the central nervous system formed during embryonic development, which could allow different classes of da neurons to develop differential connectivity to second-order neurons. We have examined the effect of Robo family members on class-specific axon lamination, and have also taken a forward genetic approach to identify new genes involved in axon and dendrite development. For the latter, we screened the third chromosome at high resolution in vivo for mutations that affect class IV da neuron morphology. Several known loci, as well as putative novel mutations, were identified that contribute to sensory dendrite and/or axon patterning. This collection of mutants, together with anatomical data on dendrites and axons, should begin to permit studies of dendrite diversity in a combined developmental and functional context, and also provide a foundation for understanding shared and distinct mechanisms that control axon and dendrite morphology.

Animals↗

PubMed2005

Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development.

A novel gene designated as fragile site-associated (FSA) gene was recently identified by positional cloning from the CHO 1q31 fragile site which plays an important role in regulating amplification of multidrug resistance (mdr1) gene in multidrug-resistant cells. FSA produces a message of approximately 16 kb which encodes an open-reading frame of 5005 amino acids. FSA shares sequence similarity with that in Caenorhabditis elegans lpd-3, a lipid storage gene. Using immunohistochemical staining and RNA in situ hybridization we report here that expression of FSA is associated with developmental programs of spermatogenesis and mammary gland in mice. Real-time RT-PCR results also support the upregulation of FSA expression in mammary gland development. Expression of FSA in many tissues including colon, skin, ovary, prostate, and bladder is mainly in the postmitotic, well-differentiated compartments. Moreover, levels of FSA expression are downregulated in tumors of these tissue origins. These results suggest that FSA also plays important roles in regulating mammalian epithelial growth and differentiation and tumor development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved protein phosphatase 2A (PP2A)-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal, cell cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.IMPORTANCEFungal pathogens must rapidly adapt their growth, morphology, and stress responses to survive within the host, requiring precise coordination of cellular signaling pathways. The conserved striatin-interacting phosphatase and kinase (STRIPAK) complex controls key developmental programs in eukaryotes, but its roles in fungal pathogenesis are not fully defined. We previously showed that STRIPAK is important for genome stability, development, and virulence in the opportunistic human fungal pathogen Cryptococcus neoformans. Here, we define how individual STRIPAK subunits differentially regulate fungal morphogenesis, genome plasticity, host adaptation, and virulence, revealing both shared and subunit-specific functions within this conserved signaling complex. Core STRIPAK mutants exhibit severe growth and stress-response defects and attenuation of virulence, whereas loss of the Mob3 subunit promotes hypervirulence by enhancing dissemination and persistence within the host. Phosphoproteomic profiling reveals that individual STRIPAK components exert shared yet distinct control over phosphorylation networks that shape host-pathogen interactions, establishing STRIPAK as a central signaling hub and a potential target for antifungal intervention.

Cryptococcus neoformans↗

PubMed2006

Cytokeratin 20 expression identifies a subtype of pancreatic adenocarcinoma with decreased overall survival.

BACKGROUND: Cytokeratins are markers of epithelial cell differentiation useful in determining histogenesis for malignancies with an unknown primary. Application of this principle to a single malignancy may identify cancer subtypes with altered developmental programs. Herein, we investigate the relevance of two widely used cytokeratins (CKs), 7 and 20, to subtype pancreas cancer and identify associations with clinical features. METHODS: A tissue microarray was constructed using tumor specimens from 103 patients who underwent resection for pancreatic adenocarcinoma with curative intent. A subset of resection specimens was evaluated for pancreatic intraepithelial neoplasia (PanIN) lesions. Tissues were immunostained by using specific anticytokeratin 7 and 20 monoclonal antibodies. RESULTS: CK 7 and 20 expression was present in 96% and 63% cases of pancreatic adenocarcinoma, respectively. Ubiquitous CK 7 expression precluded further analysis. Tumoral CK 20 expression was not associated with any histopathologic parameter but correlated with worse prognosis when considered as either a dichotomous (P=0.0098) or continuous (P=0.007) variable. In a multivariate model, tumoral CK 20 expression remained a significant independent prognosticator. CK 20 expression was absent in all PanIN lesions from eight resection specimens in which the tumor component was negative for CK 20. In contrast, presence of tumoral CK 20 was highly concordant with its expression in corresponding PanINs. CONCLUSIONS: CK 20 expression defines a subtype of pancreas cancer with important biologic properties. When present, CK 20 expression is an early event in pancreatic carcinogenesis identifiable in precursor lesions. Further studies to identify the underlying genetic changes associated with this altered developmental pathway are warranted.

Adenocarcinoma↗

PubMed1983

Specific cell-cell contact serves as the developmental signal to deactivate discoidin I gene expression in Dictyostelium discoideum.

Specific cell-cell contact is a major regulatory signal controlling cell differentiation in Dictyostelium discoideum, causing dramatic changes in the developmental program of gene expression. In this report, we focus on the relationships between specific cell-cell contact and the activity of the genes for discoidin I, an endogenous lectin that has been implicated in the cell-cell cohesion process. By performing quantitative RNA dot-hybridization assays and RNA gel blot-hybridization analyses, using as a probe a recombinant plasmid containing a discoidin I cDNA insert, we have measured changes in discoiding I mRNA levels during normal development and in response to specific manipulations of the state of cellular aggregation. Our major findings are as follows. (i) During normal development on filters, there is a close temporal correspondence between the establishment of specific cell-cell contacts and the decline in discoidin I mRNA levels. By the tight-aggregate stage, discoidin I mRNA is barely detectable. (ii) When tight aggregates are disaggregated and the cells are maintained in the disaggregated state, there is a dramatic rise in discoidin I mRNA content. (iii) When cells are developed in suspension (conditions that interfere with the establishment of tight cell-cell contacts), discoidin I mRNA accumulates to abnormally high levels, and these persist well after the levels in filter-developed cells have declined. Taken together, these results strongly suggest that cell-cell contact is the normal developmental signal to deactivate discoidin I gene expression; thus, a contact-deactivated gene for which a recombinant DNA probe is available has now been identified. Furthermore, we demonstrate that exogenous cAMP almost completely blocks the disaggregation-induced reactivation of discoidin I gene expression. Possible mechanistic relationships between specific cell-cell contact, intracellular cAMP levels, and developmental gene expression are discussed.

Journal Article↗

PubMed2006

Neural crest cell plasticity. size matters.

Patterning and morphogenesis of neural crest-derived tissues within a developing vertebrate embryo rely on a complex balance between signals acquired by neural crest cells in the neuroepithelium during their formation and signals from the tissues that the neural crest cells contact during their migration. Axial identity of hindbrain neural crest is controlled by a combinatorial pattern of Hox gene expression. Cellular interactions that pattern neural crest involve signals from the same key molecular families that regulate other aspects of patterning and morphogenesis within a developing embryo, namely the BMP, SHH and FGF pathways. The developmental program that regulates neural crest cell fate is both plastic and fixed. As a cohort of interacting cells, neural crest cells carry information that directs the axial pattern and species-specific morphology of the head and face. As individual cells, neural crest cells are responsive to signals from each other as well as from non-neural crest tissues in the environment. General rules and fundamental mechanisms have been important for the conservation of basic patterning of neural crest, but exceptions are notable and relevant. The key to furthering our understanding of important processes such as craniofacial development will require a better characterization of the molecular determinants of the endoderm, ectoderm and mesoderm and the effects that these molecules have on neural crest cell development.

Animals↗

PubMed2006

Post-transcriptional control of nuclear-encoded cytochrome oxidase subunits in Trypanosoma brucei: evidence for genome-wide conservation of life-cycle stage-specific regulatory elements.

Trypanosomes represent an excellent model for the post-transcriptional regulation of gene expression because their genome is organized into polycistronic transcription units. However, few signals governing developmental stage-specific expression have been identified, with there being no compelling evidence for widespread conservation of regulatory motifs. As a tool to search for common regulatory sequences we have used the nuclear-encoded components of the cytochrome oxidase (COX) complex of the trypanosome respiratory chain. Components of this complex represent a form of post-transcriptional operon because trypanosome mitochondrial activity is unusual in being developmentally programmed. By genome analysis we identified the genes for seven components of the COX complex. Each mRNA exhibits bloodstream stage-specific instability, which is not mediated by the RNA silencing pathway but which is alleviated by cycloheximide. Reporter assays have identified regulatory regions within the 3'-untranslated regions of three COX mRNAs operating principally at the translational level, but also via mRNA stability. Interrogation of the mapped regions via oligonucleotide frequency scoring provides evidence for genome-wide conservation of regulatory sequences among a large cohort of procyclic-enriched transcripts. Analysis of the co-regulated subunits of a stage-specific enzyme is therefore a novel approach to uncover cryptic regulatory sequences controlling gene expression at the post-transcriptional level.

3' Untranslated Regions↗