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A developmental model of infantile nystagmus.

The possibility that infantile nystagmus (IN) may reflect a failure in early sensorimotor integration has been proposed for more than a century, but is only recently being borne out in animal studies. The underlying neural and genetic substrate for this plasticity is complex. We propose that, in most cases, IN develops as a developmental response to reduced contrast sensitivity to high-spatial frequencies in an early "critical period," however caused, whether by structural malformations (e.g. foveal hypoplasia) or poor optics (e.g. cataract). As shown by psychophysics, contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina. Based on our previous theoretical study (Harris & Berry, Nonlinear Dynamics, 2006), we argue that the best compromise between moving the image and maintaining the image near the fovea (or its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity waveforms, as seen empirically. The generation of jerk waveforms relies heavily on the saccadic system, which is immature in infancy. Pendular waveforms may therefore provide an alternative to jerk waveforms, and may explain why they are seen more often in young infants. We discuss the implications of this developmental model for the need to synchronize sensory and motor developments in normal development. Failure of this synchronization may also explain some idiopathic cases.

Eye Movements↗
PubMed2004

Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development.

Il4 and Il13 encode the canonical T helper 2 (TH2) cytokines responsible both for promoting immune responses against extracellular pathogens and, when misregulated, causing allergic and autoimmune disease. The expression potential of these genes undergoes developmentally programmed repression and enhancement during commitment of naïve CD4+ T cells to the mature T helper 1 (TH1) and TH2 fates, respectively. Thus, like the globin locus, the TH2 cytokine locus provides a highly tractable system to study a developmental fate choice leading to alternative transcriptional states of either silence or permissivity. We used quantitative chromatin immunoprecipitation and RT-PCR to correlate changes in the transcriptional states of Il4 and Il13 with markers of permissive chromatin across the Il4-Il13 locus in naïve CD4+ T cells undergoing TH1 and TH2 differentiation. We provide evidence that DNaseI hypersensitive site V in the Il4 3' enhancer is the likely target for signals maintaining Il4 and Il13 transcriptional permissivity in naïve cells. We also demonstrate rapid acquisition of differences in H3 acetylation between TH1- and TH2-primed cells, indicating a developmentally early role for cytokine signaling in the process of TH cell fate determination. Finally, we show that transcriptional repression correlates with the disappearance of permissive H3 modifications from everywhere in the Il4-Il13 locus except hypersensitive site IV, suggesting a critical role for this element in the maintenance of transcriptional repression. Our findings are consistent with a progressive regulatory element activation/deactivation model of TH1/TH2 development.

Acetylation↗
PubMed2004

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

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

Amino Acid Sequence↗
PubMed2002

A review of inner ear fate maps and cell lineage studies.

A renewed interest in the development of the inner ear has provided more data on the fate and cell lineage relationships of the tissues making up this complex structure. The inner ear develops from a simple ectodermal thickening of the head called the otic placode, which undergoes a great deal of growth and differentiation to form a multichambered nonsensory epithelium that houses the six to nine sensory organs of the inner ear. Despite a large number of studies examining otic development, there have been surprisingly few fate maps generated. The published fate maps encompass four species and range from preotic to otocyst stages. Although some of these studies were consistent with a compartment and boundary model, other studies reveal extensive cell mixing during development. Cell lineage studies have been done in fewer species. At the single cell level the resulting clones in both chicks and frogs appear somewhat restricted in terms of distribution. We conclude that up until late placode stages there are no clear lineage restriction boundaries, meaning that cells seem to mix extensively at these early stages. At late placode stages, when the otic cup has formed, there are at least two boundaries located dorsally in the forming otocyst but none ventrally. These conclusions are consistent with all the fate maps and reconciles the chick and frog data. These results suggest that genes involved in patterning the inner ear may have dynamic and complex expression patterns.

Animals↗
PubMed2000

Relationship between gene expression domains of Xsnail, Xslug, and Xtwist and cell movement in the prospective neural crest of Xenopus.

The markers Xslug, Xsnail, and Xtwist all are expressed in the presumptive neural folds and are thought to delineate the presumptive neural crest. However, their interrelationship and relative spatiotemporal distributions are not well understood. Here, we present a detailed in situ hybridization analysis of the relative patterns of expression of these transcription factors from gastrulation through neurulation and post-neural crest migration. The three genes mark the prospective neural crest and roof plate, coming on sequentially, with Xsnail preceding Xslug preceding Xtwist. By combining gene expression analysis with a fate map of the same region using DiI labeling, we determined the correspondence between early and late domains of gene expression. At the beginning of gastrulation, Xsnail is present in a unique domain of expression in a lateral region of the embryo in both superficial and deep layers of the ectoderm, as are Xslug and Xtwist. During gastrulation and neurulation, the superficial layer moves faster toward the dorsal midline than the deep layer, producing a relative shift in these cell populations. By early neurula stage, the Xsnail domain is split into a medial domain in the superficial ectoderm (fated to become the roof plate) and a lateral domain in the deep layer of the ectoderm (fated to become neural crest). Xsnail is down-regulated in the most anterior neural plate and up-regulated in the posterior neural plate. Our results show that changes in the expression of Xsnail, Xslug, and Xtwist are a consequence of active cell movement in some regions coupled with dynamic changes in gene expression in other regions.

Animals↗
PubMed2006

Polycomb silencing mechanisms and genomic programming.

Polycomb complexes, best known for their role in the epigenetic silencing of homeotic genes, are now known to regulate a large number of functions in organisms from flies to man. They control transcription activators, pattern-forming genes, maintenance of stem cells and are implicated in cell proliferation and oncogenesis. Our understanding of Polycomb mechanisms derives principally from the study of homeotic genes in Drosophila, where they act in an all-or-none fashion to silence expression in inappropriate parts of the organism. This review summarizes what has been learned from homeotic genes and examines the possible extensions of Polycomb mechanisms to allow for dynamic regulatory behavior and the reprogramming of silenced chromatin states.

Animals↗
PubMed2006

Information theory in living systems, methods, applications, and challenges.

Living systems are distinguished in nature by their ability to maintain stable, ordered states far from equilibrium. This is despite constant buffeting by thermodynamic forces that, if unopposed, will inevitably increase disorder. Cells maintain a steep transmembrane entropy gradient by continuous application of information that permits cellular components to carry out highly specific tasks that import energy and export entropy. Thus, the study of information storage, flow and utilization is critical for understanding first principles that govern the dynamics of life. Initial biological applications of information theory (IT) used Shannon's methods to measure the information content in strings of monomers such as genes, RNA, and proteins. Recent work has used bioinformatic and dynamical systems to provide remarkable insights into the topology and dynamics of intracellular information networks. Novel applications of Fisher-, Shannon-, and Kullback-Leibler informations are promoting increased understanding of the mechanisms by which genetic information is converted to work and order. Insights into evolution may be gained by analysis of the the fitness contributions from specific segments of genetic information as well as the optimization process in which the fitness are constrained by the substrate cost for its storage and utilization. Recent IT applications have recognized the possible role of nontraditional information storage structures including lipids and ion gradients as well as information transmission by molecular flux across cell membranes. Many fascinating challenges remain, including defining the intercellular information dynamics of multicellular organisms and the role of disordered information storage and flow in disease.

Computational Biology↗
PubMed2005

C. elegans daf-6 encodes a patched-related protein required for lumen formation.

Sensory organs are often composed of neuronal sensory endings accommodated in a lumen formed by ensheathing epithelia or glia. Here we show that lumen formation in the C. elegans amphid sensory organ requires the gene daf-6. daf-6 encodes a Patched-related protein that localizes to the luminal surfaces of the amphid channel and other C. elegans tubes. While daf-6 mutants display only amphid lumen defects, animals defective for both daf-6 and the Dispatched gene che-14 exhibit defects in all tubular structures that express daf-6. Furthermore, DAF-6 protein is mislocalized, and lumen morphogenesis is abnormal, in mutants with defective sensory neuron endings. We propose that amphid lumen morphogenesis is coordinated by neuron-derived cues and a DAF-6/CHE-14 system that regulates vesicle dynamics during tubulogenesis.

Animals↗
PubMed2003

Functional genomics of ageing.

Ageing is the most complex phenotype currently known, since it becomes manifest in all organs and tissues, affects an organism's entire physiology, impacts function at all levels and increases susceptibility to all major chronic diseases. Insight into the molecular and cellular targets of the ageing process would offer the unprecedented opportunity to postpone and prevent some, if not all, of its deteriorative aspects by preventive and therapeutic means. Thus far, our understanding of the causes of ageing is limited. To an important extent this is due to our inability, in the past, to study ageing systems. Instead, ample information has been gathered about individual cellular components at various ages, but this has not allowed a clear understanding of the integrated genomic circuits that control mechanisms of ageing, survival and stress responses. With the emergence of functional genomics, we finally have the opportunity to study ageing in a comprehensive manner, as a function of the dynamic network of genes that determines the physiology of an individual organism over time.

Aging↗
PubMed2002

Plasmodesmata: dynamic regulation and role in macromolecular cell-to-cell signaling.

Recent studies have demonstrated the functional significance of intercellular RNA and protein trafficking in plant development, confirming the role of plasmodesmata (PD) in the mediation and control of intercellular communication via macromolecules. Small fluorescent tracer loading techniques and experiments involving the expression of proteins tagged with green fluorescent protein (GFP) have been used to investigate the mechanisms of PD targeting and trafficking, as well as to elucidate the dynamic and structural properties of these channels.

Actins↗
PubMed2005

Are fluctuating asymmetry studies adequately sampled? Implications of a new model for size distribution.

Previous work on fluctuating asymmetry (FA) has highlighted its controversial relationship with environmental stress and genetic architecture. While size-based measures of FA have been assumed to have half-normal distributions within populations, studies of model developmental mechanisms have suggested other plausible distributions for FA. We investigated the distribution of FA in large empirical data sets of wing shape and wing size asymmetry from three species of insects (cotton aphid Aphis gossipyii Glover, honeybee Apis mellifera, and long-legged fly Chrysosoma crinitus). Regardless of measurement method, FA was best described by a double Pareto-lognormal (DPLN) distribution or one of its limiting functional forms. To investigate convergence of mean sample FA to the population mean at various sample sizes, we sampled repeatedly under a DPLN distribution using parameter values that best fitted our data. Sample variances are much larger, and hence, convergence is slowed considerably with univariate or multivariate size-based measures of FA in contrast to a multivariate shape-based measure of FA. We suggest that much of the past work on FA may be undersampled, and we recommend using multivariate shape-based approaches or collecting larger data sets in future studies. We also discuss the implications of the DPLN distribution for understanding the developmental mechanisms underlying FA.

Animals↗
PubMed2001

Effects of nutritional factors and soil addition on growth, longevity and fecundity of the tadpole shrimp Triops newberryi (Notostraca: Triopsidae), a potential biological control agent of immature mosquitoes.

The notostracan tadpole shrimp (TPS) Triops newberryi Packard has potential to be used as a biocontrol agent of immature mosquitoes. Eggs, nymphal or adult shrimps are considered to be the stages for field introduction. To yield good growth of the shrimp and high production of shrimp eggs under artificial conditions, nutritional requirements of TPS for growth, survival and fecundity need to be elucidated. In the laboratory, we evaluated various nutritional and edaphic regimens, such as soil alone, mosquito larvae or rabbit pellets alone and various combinations of these three components for culturing. These factors influenced the growth, longevity and egg production profoundly. It was shown that the simulated natural conditions, i.e. full combination of all three factors, yielded the largest TPS with longest survival and highest egg production, followed by the combinations of any two components. Any single component, soil, mosquito larvae, or rabbit pellets, did not result in good growth, survival and egg production. By formulating optimal rearing substrates, this species of TPS will yield large numbers of all stages for experimentation and field introductions. Under optimal conditions, they mature in 7-8 days and survive for about one month. Each TPS is capable of producing up to 1,000 eggs during its lifetime. These studies developed nutritional regimens for TPS mass culturing procedures, where the eggs, nymphal and adult TPS can be mass cultured for field introduction and stocking in mosquito developmental sites.

Animal Feed↗
PubMed1996

Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions.

We describe the cloning of the mouse glial cell line-derived neurotrophic factor (GDNF) gene and its expression during embryogenesis. GDNF is a distant member of the superfamily of TGF-beta related genes that was originally identified on the basis of its striking neurotrophic activity. GDNF is expressed in a highly dynamic pattern in the anterior neuroectoderm during early stages of neurogenesis between E7.5 and E10.5. Beginning at E10.5 GDNF is also expressed in several organs that develop through inductive epithelial-mesenchymal interactions. In those organs, GDNF expression is strictly confined to mesenchymal tissues and is not found in epithelia. Our results suggest multiple roles for GDNF during early stages of neuronal development and in epithelial-mesenchymal interactions.

Amino Acid Sequence↗
PubMed2006

Sexually dimorphic expression of secreted frizzled-related (SFRP) genes in the developing mouse Müllerian duct.

In developing male embryos, the female reproductive tract primordia (Müllerian ducts) regress due to the production of testicular anti-Müllerian hormone (AMH). Because of the association between secreted frizzled-related proteins (SFRPs) and apoptosis, their reported developmental expression patterns and the role of WNT signaling in female reproductive tract development, we examined expression of Sfrp2 and Sfrp5 during development of the Müllerian duct in male (XY) and female (XX) mouse embryos. We show that expression of both Sfrp2 and Sfrp5 is dynamic and sexually dimorphic. In addition, the male-specific expression observed for both genes prior to the onset of regression is absent in mutant male embryos that fail to undergo Müllerian duct regression. We identified ENU-induced point mutations in Sfrp5 and Sfrp2 that are predicted to severely disrupt the function of these genes. Male embryos and adults homozygous for these mutations, both individually and in combination, are viable and apparently fertile with no overt abnormalities of reproductive tract development.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Immunohistological localization of the adhesion molecules L1, N-CAM, and MAG in the developing and adult optic nerve of mice.

The localization of the cell adhesion molecules L1, neural cell adhesion molecule (N-CAM), and myelin-associated glycoprotein (MAG) was studied immunohistologically at the light and electron microscopic levels and immunochemically in the developing and adult mouse optic nerve and retina. The neural adhesion molecule L1 is strongly expressed on the shafts of fasciculating unmyelinated axons at all ages studied from embryonic day 15 through adulthood. Growth cones of retinal ganglion cell axons were weakly L1-positive or L1-negative when contacting glial cells. Unmyelinated axons were not only L1-positive when contacting each other but also when contacting glia, whereas contacts between glial cells were L1-negative at all developmental unmyelinated retinal nerve fiber layer or in the unmyelinated optic nerve head became L1-negative when enwrapped by myelin in the optic nerve proper. At all stages of development N-CAM showed profuse labeling on fasciculating axons, growth cones, and their contact sites with glial cells as well as contacts between glial cells. In contrast to L1, axons remained N-CAM-positive when becoming myelinated. Sometimes, N-CAM was found in compact myelin. However, N-CAM was absent from glial surfaces contacting basement membranes at the interface to meninges, blood vessels, and the vitreous body of the eye. MAG was first detectable intracellularly in oligodendrocytes associated with the endoplasmic reticulum and Golgi apparatus before it became apparent at the cell surface. There it was present on oligodendrocytes prior and during the first stages of ensheathment of axons, both on cell body and processes. After formation of compact myelin MAG remained strongly expressed periaxonally and was only weakly detectable in noncompacted myelin including inner mesaxon and paranodal loops. None of the adhesion molecules was detectable on extracellular matrix, in the meninges, or on endothelial cells. Immunochemical analysis of antigen expression at different developmental stages was in agreement with the immunohistological data. We infer from these observations that L1 is involved in stabilization not only of axon-axon, but also axon-glia contacts, while the more dynamic structure of the growth cone generally expresses less L1. A differential expression of L1 along the course of an axon--being present on its unmyelinated, but absent on its myelinated part--further supports the notion that L1 may be involved in the stabilization of axonal fascicles but not of axon-myelin contacts.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed2005

Peer interaction: what causes what?

Peer interaction is examined as a source of behavior change in children and adolescents. The dynamics of peer influence are discussed in terms of six issues: characteristics of the influence source; characteristics of the child or adolescent being influenced; the relationship existing between influence source and the individual being influenced; developmental change; processes underlying peer influence; and constraints deriving from the behavior domain being examined. Research shows that contact with peers has complex effects on individual behavior, and numerous moderators and mediators must be considered in order to account for them. The discussion is linked to the papers included in this special issue.

Adolescent↗
PubMed2006

HMG chromosomal proteins in development and disease.

The high mobility group (HMG) proteins are a superfamily of abundant and ubiquitous nuclear proteins that bind to DNA and nucleosomes and induce structural changes in the chromatin fiber. They are important in chromatin dynamics and influence DNA processing in the context of chromatin. Results emerging from studies of human disease, genetically modified mice and cells with altered HMG expression indicate that the expression of the HMG proteins is developmentally regulated and that changes in HMG protein levels alter the cellular phenotype and can lead to developmental abnormalities and disease. Here, we focus on the biological function of HMG proteins and highlight their possible roles in cellular differentiation and in the etiology of various diseases.

Animals↗