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PubMed2001

Pax group III genes and the evolution of insect pair-rule patterning.

Pair-rule genes were identified and named for their role in segmentation in embryos of the long germ insect Drosophila. Among short germ insects these genes exhibit variable expression patterns during segmentation and thus are likely to play divergent roles in this process. Understanding the details of this variation should shed light on the evolution of the genetic hierarchy responsible for segmentation in Drosophila and other insects. We have investigated the expression of homologs of the Drosophila Pax group III genes paired, gooseberry and gooseberry-neuro in short germ flour beetles and grasshoppers. During Drosophila embryogenesis, paired acts as one of several pair-rule genes that define the boundaries of future parasegments and segments, via the regulation of segment polarity genes such as gooseberry, which in turn regulates gooseberry-neuro, a gene expressed later in the developing nervous system. Using a crossreactive antibody, we show that the embryonic expression of Pax group III genes in both the flour beetle Tribolium and the grasshopper Schistocerca is remarkably similar to the pattern in Drosophila. We also show that two Pax group III genes, pairberry1 and pairberry2, are responsible for the observed protein pattern in grasshopper embryos. Both pairberry1 and pairberry2 are expressed in coincident stripes of a one-segment periodicity, in a manner reminiscent of Drosophila gooseberry and gooseberry-neuro. pairberry1, however, is also expressed in stripes of a two-segment periodicity before maturing into its segmental pattern. This early expression of pairberry1 is reminiscent of Drosophila paired and represents the first evidence for pair-rule patterning in short germ grasshoppers or any hemimetabolous insect.

Amino Acid Sequence↗
PubMed2002

A mitogen gradient of dorsal midline Wnts organizes growth in the CNS.

Cell cycle progression and exit must be precisely patterned during development to generate tissues of the correct size, shape and symmetry. Here we present evidence that dorsal-ventral growth of the developing spinal cord is regulated by a Wnt mitogen gradient. Wnt signaling through the beta-catenin/TCF pathway positively regulates cell cycle progression and negatively regulates cell cycle exit of spinal neural precursors in part through transcriptional regulation of cyclin D1 and cyclin D2. Wnts expressed at the dorsal midline of the spinal cord, Wnt1 and Wnt3a, have mitogenic activity while more broadly expressed Wnts do not. We present several lines of evidence suggesting that dorsal midline Wnts form a dorsal to ventral concentration gradient. A growth gradient that correlates with the predicted gradient of mitogenic Wnts emerges as the neural tube grows with the proliferation rate highest dorsally and the differentiation rate highest ventrally. These data are rationalized in a 'mitogen gradient model' that explains how proliferation and differentiation can be patterned across a growing field of cells. Computer modeling demonstrates this model is a robust and self-regulating mechanism for patterning cell cycle regulation in a growing tissue. Supplemental data available on-line

Animals↗
PubMed1999

The CNS midline cells and spitz class genes are required for proper patterning of Drosophila ventral neuroectoderm.

The Drosophila embryonic central nervous system (CNS) develops from sets of neuroblasts (NBs) which segregate from the ventral neuroectoderm during early embryogenesis. It is not well established how each individual NB in the neuroectoderm acquires its characteristic identity along the dorsal-ventral axis. Since it is known that CNS midline cells and spitz class genes (pointed, rhomboid, single-minded, spitz and Star) are required for the proper patterning of ventral CNS and epidermis originated from the ventral neuroectoderm, this study was carried out to determine the functional roles of the CNS midline cells and spitz class genes in the fate determination of ventral NBs and formation of mature neurons and their axon pathways. Several molecular markers for the identified NBs, neurons, and axon pathways were employed to examine marker gene expression profile, cell lineage and axon pathway formation in the spitz class mutants. This analysis showed that the CNS midline cells specified by single-minded gene as well as spitz class genes are required for identity determination of a subset of ventral NBs and for formation of mature neurons and their axon pathways. This study suggests that the CNS midline cells and spitz class genes are necessary for proper patterning of the ventral neuroectoderm along the dorsal-ventral axis.

Animals↗
PubMed2001

Detailed field pattern is intrinsic to the embryonic mouse hippocampus early in neurogenesis.

There is accumulating evidence that the mammalian cerebral cortex is regionally specified early in neurogenesis. However, the degree and scale of the regional pattern that is intrinsic to different parts of the cortical primordium remains unclear. Here, we show that detailed patterning-the accurate positioning of several areas or fields-is intrinsic to the part of the primordium that generates the hippocampus. A caudomedial portion of the cortical primordium, the site from which the hippocampus arises, was isolated from potential extrinsic patterning cues by maintaining it in explant culture. Explants were prepared at embryonic day (E) 12.5, which is early in hippocampal neurogenesis in the mouse and 3 d before individual fields are seen by differential gene expression. Allowed to develop for 3 d in vitro, E12.5 explants upregulate field-specific patterns of gene expression with striking temporal and spatial accuracy. Possible sources of patterning signals intrinsic to the explants were evaluated by removing the cortical hem or presumptive extrahippocampal cortex from the explants. To expose cells to different local positional cues, explant fragments were grafted into ectopic positions in a larger explant. None of these manipulations altered the development of patterned, field-specific gene expression. Finally, explants harvested at E10.5 also upregulate field-specific gene expression, although less robustly. Some hippocampal patterning information is therefore intrinsic to the caudomedial cortical primordium at the time that the first hippocampal neurons are born at E10.5. By E12.5, hippocampal field patterning appears to be well established and resistant to the manipulation of several potential intrinsic cues.

Animals↗
PubMed2001

Fox (forkhead) genes are involved in the dorso-ventral patterning of the Xenopus mesoderm.

Fox (forkhead/winged helix) genes encode a family of transcription factors that are involved in embryonic pattern formation, regulation of tissue specific gene expression and tumorigenesis. Several of them are transcribed during Xenopus embryogenesis and are important for the patterning of ectoderm, mesoderm and endoderm. We have isolated three forkhead genes that are activated during gastrulation and play an important role in the dorso-ventral patterning of the mesoderm. XFKH1 (FoxA4b), the first vertebrate forkhead gene to be implicated in embryonic pattern formation, is expressed in the Spemann-Mangold organizer region and later in the embryonic notochord. XFKH7, the Xenopus orthologue of the murine Mfh1(Foxc2), is expressed in the presomitic mesoderm, but not in the notochord or lateral plate mesoderm. Finally, XFD-13'(FoxF1b)1 is expressed in the lateral plate mesoderm, but not in the notochord or presomitic mesoderm. Expression pattern and functional experiments indicate that these three forkhead genes are involved in the dorso-ventral patterning of the mesoderm.

Amino Acid Sequence↗
PubMed2001

Otx2 and HNF3beta genetically interact in anterior patterning.

Patterning the developing nervous system in the mouse has been proposed to depend on two separate sources of signals, the anterior visceral endoderm (AVE) and the node or organizer. Mutation of the winged-helix gene HNF3beta leads to loss of the node and its derivatives, while mutation of the homeobox gene Otx2 results in loss of head structures, apparently at least partially because of defects in the AVE. To investigate the potential genetic interactions between the two signaling centers, we crossed Otx2+/- and HNF3beta+/- mice and found that very few Otx2+/-;HNF3beta+/- double heterozygous mutants survived to weaning. Normal Mendelian ratios of genotypes were observed during gestation, but more than half the double heterozygotes displayed a severe anterior patterning phenotype that would be incompatible with postnatal survival. The phenotype was characterized by varying degrees of holoprosencephaly, cyclopia with proboscis-like structures, and anterior forebrain truncations. Regional marker analysis revealed that ventral forebrain structures of Otx2+/-;HNF3beta+/- mutant embryos were most severely affected. Shh expression was completely absent in the anterior region of Otx2+/-;HNF3beta+/- embryos, suggesting that Otx2 and HNF3beta genetically interact, directly or indirectly, to regulate Shh expression in the anterior midline. In addition, the forebrain truncations suggest an involvement of both genes in anterior patterning, through their overlapping expression domains in either the AVE and/or the prechordal mesoderm.

Animals↗
PubMed2004

Obsessive-compulsive disorder and body dysmorphic disorder: a comparison of clinical features.

Body dysmorphic disorder (BDD) is currently classified as a somatoform disorder in DSM-IV, but has been long noted to have some important similarities with obsessive-compulsive disorder (OCD). In addition, BDD and OCD have been often reported to be comorbid with each other. In the present study, we compared demographic characteristics, clinical features and psychiatric comorbidity in patients with OCD, BDD or comorbid BDD-OCD (34 subjects with BDD, 79 with OCD and 24 with BDD-OCD). We also compared the pattern of body dysmorphic concerns and associated behaviors in BDD patients with or without OCD comorbidity. In our sample, BDD and OCD groups showed similar sex ratio. Both groups with BDD and BDD-OCD were significantly younger, and experienced the onset of their disorder at a significantly younger age than subjects with OCD. The two BDD groups were also less likely to be married, and more likely to be unemployed and to have achieved lower level degree, than OCD subjects even when controlling for age. The three groups were significantly different in the presence of comorbid bulimia, alcohol-related and substance-use disorders, BDD-OCD patients showing the highest rate and OCD the lowest. BDD-OCD reported more comorbid bipolar II disorder and social phobia than in the other two groups, while generalized anxiety disorder was observed more frequently in OCD patients. Patients with BDD and BDD-OCD were similar as regards the presence of repetitive BDD-related behaviors, such as mirror-checking or camouflaging. Both groups also did show a similar pattern of distribution as regards the localization of the supposed physical defects in specific areas of the body. The only significant difference concerned the localization in the face, that was more frequent in the BDD group. Our results do not contradict the proposed possible conceptualization of BDD as an OCD spectrum disorder. However, BDD does not appear to be a simple clinical variant of OCD and it seems to be also related to social phobia, mood, eating and impulse control disorders. The co-presence of BDD and OCD features appears to possibly individuate a particularly severe form of the syndrome, with a greater load of psychopathology and functional impairment and a more frequent occurrence of other comorbid mental disorders.

Adult↗
PubMed2006

Global cell sorting in the C. elegans embryo defines a new mechanism for pattern formation.

4D microscopic observations of Caenorhabditis elegans development show that the nematode uses an unprecedented strategy for development. The embryo achieves pattern formation by sorting cells, through far-ranging movements, into coherent regions before morphogenesis is initiated. This sorting of cells is coupled to their particular fate. If cell identity is altered by experiment, cells are rerouted to positions appropriate to their new fates even across the whole embryo. This cell behavior defines a new mechanism of pattern formation, a mechanism that is also found in other animals. We call this new mechanism "cell focusing". When the fate of cells is changed, they move to new positions which also affect the shape of the body. Thus, this process is also important for morphogenesis.

Animals↗
PubMed1998

Hoxc13 mutant mice lack external hair.

Hox genes are usually expressed temporally and spatially in a colinear manner with respect to their positions in the Hox complex. Consistent with the expected pattern for a paralogous group 13 member, early embryonic Hoxc13 expression is found in the nails and tail. Hoxc13 is also expressed in vibrissae, in the filiform papillae of the tongue, and in hair follicles throughout the body; a pattern that apparently violates spatial colinearity. Mice carrying mutant alleles of Hoxc13 have been generated by gene targeting. Homozygotes have defects in every region in which gene expression is seen. The most striking defect is brittle hair resulting in alopecia (hairless mice). One explanation for this novel role is that Hoxc13 has been recruited for a function common to hair, nail, and filiform papilla development.

Animals↗
PubMed1991

Regional variation in adipose tissue lipoprotein lipase activity: association with plasma high density lipoprotein levels.

The associations of adipose tissue lipoprotien lipase (AT-LPL) activity with body fatness and plasma lipoprotein levels were studied in the light of the recently described regional differences in AT-LPL activity. In this regard, heparin-releasable LPL activity was measured in abdominal and femoral adipose tissues of 29 pre-menopausal women. Body fatness variables were all positively correlated with abdominal and femoral AT-LPL activities expressed per 10(6) cells. However, abdominal and femoral AT-LPL activities expressed per unit of cell surface displayed divergent association patterns with body fatness and plasma lipoprotein levels. Indeed, only abdominal AT-LPL activity remained significantly correlated with body fatness variables after adjustment for fat cell surface. Furthermore, whereas abdominal AT-LPL activity tended to be negatively correlated with plasma HDL-cholesterol levels, femoral AT-LPL activity was positively correlated with plasma HDL2-cholesterol (r = 0.40, P less than 0.05) concentration and with the HDL2-cholesterol/HDL3-cholesterol ratio (r = 0.49, P less than 0.01). These results demonstrate the importance of taking into account the regional variation in metabolic activity of adipose tissue when studying its associations with body fatness, and with plasma lipoprotein levels. The lack of association between abdominal AT-LPL activity and plasma HDL2-cholesterol levels lead us to suggest that AT-LPL activity may not be causally related with plasma HDL levels.

Adipose Tissue↗
PubMed1998

Tail-flip mechanism and size-dependent kinematics of escape swimming in the brown shrimp crangon crangon

Tail-flip escape swimming by the brown shrimp Crangon crangon has been investigated across a range of body lengths (11-69 mm) using high-speed video analysis. This has revealed several novel aspects of the tail-flip mechanism when compared with that of other decapod crustaceans that have been studied. (i) The pattern of body flexion in C. crangon produces movement of the cephalothorax as well as the abdomen about the centre of mass. (ii) Shrimps form a 'head-fan' with their antennal scales, in addition to the tail-fan formed by their uropods, apparently for generating thrust during tail-flips. (iii) Shrimps typically swim on their side rather than in an upright body position. It is suggested that these features may be interlinked and derive from habitat specialisation. The kinematic properties of tail-flips were found to vary with shrimp size. As shrimp body length increased, the rate of body flexion and re-extension decreased whilst the duration of tail-flips increased. Mean (and maximum) velocity estimates ranged between 0.4 m s-1 (0.7 m s-1) and 1.1 m s-1 (1.8 m s-1) for shrimps of different sizes. The combined effects of escape behaviour and size-dependent variability in tail-flip kinematics will have important implications with regard to predation risk.

Journal Article↗
PubMed1993

Abdominal body mass distribution and elevated blood pressure are associated with increased risk of death from cardiovascular diseases and cancer in middle-aged men. The results of a 15- to 20-year follow-up in the Paris prospective study I.

The associations of blood pressure (BP), body mass index (BMI) and iliac-to-thigh circumference index (CI) with total, cardiovascular and cancer mortality were investigated in 7312 middle-aged men, initially free of coronary heart disease, known cancer and not treated for hypertension, who have been followed for 15 to 20 years in the Paris prospective study I. Using Cox survival regression analysis, total mortality (1208 deaths) was found to be highest in relatively lean men (BMI < 24.4 kg/m2) with elevated blood pressure (mean BP > or = 96 mmHg) and central pattern of body mass distribution (CI > 1.82). Cancer causes accounted for a large proportion of the increased mortality risk. In parallel, mortality from cardiovascular diseases increased independently with blood pressure and iliac-to-thigh circumference index, but increased with body mass index only in men with low blood pressure (mean BP < 96 mmHg). Taking into account serum cholesterol and cigarette smoking levels as covariates and excluding deaths occurring 5 to 10 years after the examination only slightly attenuated the intensity of this pattern of association.

Abdomen↗
PubMed1997

Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system.

Molecular gradients have been postulated to control the topographic mapping of retinal axons in their central targets. Based initially on their expression patterns, and more recently on functional studies, members of the EphA subfamily of receptor tyrosine kinases and their ephrin-A ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum. The report that a receptor of the EphB subfamily, EphB2/Cek5/Nuk/Sek3, is expressed in a high ventral to low dorsal gradient in the developing chick retina and is present on ganglion cell axons suggests that it may be involved in the mapping of retinal axons along the corresponding dorsal-ventral axis of the tectum. To address this issue, we have determined the expression and distribution of ephrin-B1/LERK-2/Cek5-L and ephrin-B2/LERK-5/Htk-L/ELF-2, ligands for EphB2, in the developing chick retinotectal system using riboprobes, immunocytochemistry, and receptor affinity probes. Both ephrin-B1 and ephrin-B2 transcripts are expressed in a high dorsal to low ventral gradient in the developing retina, complementary to the distribution of EphB2. Ephrin-B1 and ephrin-B2 proteins are predominantly found in the developing plexiform layers, suggesting a role in the development of intraretinal connections. Neither protein is detected on ganglion cell axons. In tectum, ephrin-B1 transcripts are expressed in a high dorsal to low ventral gradient in the neuroepithelium and the protein is present along the processes of radial glia and is concentrated at their endfeet in the stratum opticum, at the time retinal axons are growing through it. This distribution of ephrin-B1 suggests that it influences retinal axon mapping along the dorsal-ventral tectal axis and may also be involved in intratectal development. In contrast, ephrin-B2 transcripts and protein are localized to the deeper retinorecipient laminae in the tectum at the time retinal axons begin to arborize in them, suggesting that this ligand may influence the laminar patterning of retinal axon terminations.

Animals↗
PubMed1998

Control of dorsoventral somite patterning by Wnt-1 and beta-catenin.

In vertebrates, the dorsoventral patterning of somitic mesoderm is controlled by factors expressed in adjacent tissues. The ventral neural tube and the notochord function to promote the formation of the sclerotome, a ventral somite derivative, while the dorsal neural tube and the surface ectoderm have been shown to direct somite cells to a dorsal dermomyotomal fate. A number of signaling molecules are expressed in these inducing tissues during times of active cell fate specification, including members of the Hedgehog, Wnt, and BMP families. However, with the exception of the ventral determinant Sonic hedgehog (Shh), the functions of these signaling molecules with respect to dorsoventral somite patterning have not been determined. Here we investigate the role of Wnt-1, a candidate dorsalizing factor, in the regulation of sclerotome and dermomyotome formation. When ectopically expressed in the presomitic mesoderm of chick embryos in ovo, Wnt-1 differentially affects the expression of dorsal and ventral markers. Specifically, ectopic Wnt-1 is able to completely repress ventral (sclerotomal) markers and to enhance and expand the expression of dorsal (dermomyotomal) markers. However, Wnt-1 appears to be unable to convert all somitic mesoderm to a dermomyotomal fate. Delivery of an activated form of beta-catenin to somitic mesoderm mimics the effects of Wnt-1, demonstrating that Wnt-1 likely acts directly on somitic mesoderm, and not through adjacent tissues via an indirect signal relay mechanism. Taken together, our results support a model for somite patterning where sclerotome formation is controlled by the antagonistic activities of Shh and Wnt signaling pathways.

Animals↗
PubMed2004

A new interpretation of the Keller-Segel model based on multiphase modelling.

In this paper an alternative derivation and interpretation are presented of the classical Keller-Segel model of cell migration due to random motion and chemotaxis. A multiphase modelling approach is used to describe how a population of cells moves through a fluid containing a diffusible chemical to which the cells are attracted. The cells and fluid are viewed as distinct components of a two-phase mixture. The principles of mass and momentum balance are applied to each phase, and appropriate constitutive laws imposed to close the resulting equations. A key assumption here is that the stress in the cell phase is influenced by the concentration of the diffusible chemical. By restricting attention to one-dimensional cartesian geometry we show how the model reduces to a pair of nonlinear coupled partial differential equations for the cell density and the chemical concentration. These equations may be written in the form of the Patlak-Keller-Segel model, naturally including density-dependent nonlinearities in the cell motility coefficients. There is a direct relationship between the random motility and chemotaxis coefficients, both depending in an inter-related manner on the chemical concentration. We suggest that this may explain why many chemicals appear to stimulate both chemotactic and chemokinetic responses in cell populations. After specialising our model to describe slime mold we then show how the functional form of the chemical potential that drives cell locomotion influences the ability of the system to generate spatial patterns. The paper concludes with a summary of the key results and a discussion of avenues for future research.

Body Patterning↗
PubMed2005

Engrailed is expressed in larval development and in the radial nervous system of Patiriella sea stars.

We documented expression of the pan-metazoan neurogenic gene engrailed in larval and juvenile Patiriella sea stars to determine if this gene patterns bilateral and radial echinoderm nervous systems. Engrailed homologues, containing conserved En protein domains, were cloned from the radial nerve cord. During development, engrailed was expressed in ectodermal (nervous system) and mesodermal (coeloms) derivatives. In larvae, engrailed was expressed in cells lining the larval and future adult coeloms. Engrailed was not expressed in the larval nervous system. As adult-specific developmental programs were switched on during metamorphosis, engrailed was expressed in the central nervous system and peripheral nervous system (PNS), paralleling the pattern of neuropeptide immunolocalisation. Engrailed was first seen in the developing nerve ring and appeared to be up-regulated as the nervous system developed. Expression of engrailed in the nerve plexus of the tube feet, the lobes of the hydrocoel along the adult arm axis, is similar to the reiterated pattern of expression seen in other animals. Engrailed expression in developing nervous tissue reflects its conserved role in neurogenesis, but its broad expression in the adult nervous system of Patiriella differs from the localised expression seen in other bilaterians. The role of engrailed in patterning repeated PNS structures indicates that it may be important in patterning the fivefold organisation of the ambulacrae, a defining feature of the Echinodermata.

Amino Acid Sequence↗
PubMed2006

Mechanisms of lineage segregation in the avian dermomyotome.

The somite and its intermediate derivatives, sclerotome and dermomyotome (DM), are composed of distinct subdomains based on lineage analysis and gene expression patterns. This sets the grounds for elucidating the mechanisms underlying differential cell specification and morphogenesis. By examining the in vivo roles of N-cadherin on discrete domains of the somitic epithelium at various times, our recent studies highlight the existence of a regional and temporal heterogeneity in cellular responsiveness. As examples of this assortment, we document a coupling between asymmetric cell division and fate segregation in the DM sheet, sequential effects of N-cadherin-mediated adhesion on early myogenic specification compared to later myofiber patterning, and a differential behavior of pioneer myoblasts compared to later myogenic waves.

Animals↗
PubMed1999

Reissner's substance expressed as a transient pattern in vertebrate floor plate.

The function of the floor plate in dorso-ventral patterning of the developing nervous system and in the guidance of commissural axons is well established. However, several morphological aspects concerning the exact localization of its rostral and caudal end and the regional and temporal specialization are still controversial. We present new insights revealed by the expression of Reissner's substance in the floor plate during early neurogenesis of zebrafish, Xenopus, chick and rat. We used a polyclonal antiserum raised against Reissner's substance, which is a secretory product of radial glia in the roof plate of the adult vertebrate brain. In early embryonic stages the rostral boundary of floor plate immunoreaction vary in the different vertebrates. Immunoreactive cells are not only present in the epichordal region (rat) but also in prechordal areas of the midbrain (chick) and forebrain (zebrafish and Xenopus). During further development, Reissner's substance expression disappears first in the most rostral areas and later also in the spinal cord. However, immunopositive labelling in the isthmus region at the mes-metencephalic boundary, described originally as the flexural organ, is most extensive and detectable during a long period of embryonic development. It is proposed that the gradual restriction of Reissner's substance expression to the isthmus reflects the complex differentiation processes in this region also in later embryonic development. Furthermore, the expression pattern in zebrafish indicates that Reissner's substance could play a role in axonal decussation.

Animals↗