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PubMed1999

Relation of circumferences and skinfold thicknesses to lipid and insulin concentrations in children and adolescents: the Bogalusa Heart Study.

BACKGROUND: Although body fat patterning has been related to adverse health outcomes in adults, its importance in children and adolescents is less certain. OBJECTIVE: We examined the relation of circumference (waist and hip) and skinfold-thickness (subscapular and triceps) measurements to lipid and insulin concentrations among 2996 children and adolescents aged 5-17 y. DESIGN: This was a community-based, cross-sectional study conducted in 1992-1994. RESULTS: A central or abdominal distribution of body fat was related to adverse concentrations of triacylglycerol, LDL cholesterol, HDL cholesterol, and insulin; these associations were independent of race, sex, age, weight, and height. These associations were observed whether fat patterning was characterized by using 1) waist circumference alone (after adjustment for weight and height), 2) waist-to-hip ratio, or 3) principal components analysis. Compared with a child at the 10th percentile of waist circumference, a child at the 90th percentile was estimated to have, on average, higher concentrations of LDL cholesterol (0.17 mmol/L), triacylglycerol (0.11 mmol/L), and insulin (6 pmol/L) and lower concentrations of HDL cholesterol (-0.07 mmol/L). These differences, which were independent of weight and height, were significant at the 0.001 level and were consistent across race-sex groups. CONCLUSIONS: These findings emphasize the importance of obtaining information on body fat distribution, waist circumference in particular, in children. Waist circumference, which is relatively easy to measure, may help to identify children likely to have adverse concentrations of lipids and insulin.

Adipose Tissue↗
PubMed2006

On the origins of morphological disparity and its diverse developmental bases.

It has been repeatedly claimed that morphological novelties are an unresolved problem in evolutionary theory. Several definitions of novelty exist but most emphasize that novelties imply qualitative changes on the phenotype and not the quantitative gradual changes favored in the neo-Darwinian approach to evolutionary theory. This article discusses how the concept of novelty is used to describe aspects of morphological evolution that are not satisfactorily explained under the modern synthesis. In this article, it is suggested that there is a repertoire of morphological changes rather than two discrete qualitatively different types of morphological change. How these different types of morphological changes can be understood from the diversity of developmental mechanisms existing in animal development is explored. Specifically, it is proposed that animal morphology and its variation can be understood from the spatial patterns produced by a set of basic developmental mechanisms and their combination. Some specific examples of these kinds of morphologic changes are explained.

Animals↗
PubMed2006

Developmental constraints vs. variational properties: How pattern formation can help to understand evolution and development.

This article suggests that apparent disagreements between the concept of developmental constraints and neo-Darwinian views on morphological evolution can disappear by using a different conceptualization of the interplay between development and selection. A theoretical framework based on current evolutionary and developmental biology and the concepts of variational properties, developmental patterns and developmental mechanisms is presented. In contrast with existing paradigms, the approach in this article is specifically developed to compare developmental mechanisms by the morphological variation they produce and the way in which their functioning can change due to genetic variation. A developmental mechanism is a gene network, which is able to produce patterns in space though the regulation of some cell behaviour (like signalling, mitosis, apoptosis, adhesion, etc.). The variational properties of a developmental mechanism are all the pattern transformations produced under different initial and environmental conditions or IS-mutations. IS-mutations are DNA changes that affect how two genes in a network interact, while T-mutations are mutations that affect the topology of the network itself. This article explains how this new framework allows predictions not only about how pattern formation affects variation, and thus phenotypic evolution, but also about how development evolves by replacement between pattern formation mechanisms. This article presents testable inferences about the evolution of the structure of development and the phenotype under different selective pressures. That is what kind of pattern formation mechanisms, in which relative temporal order, and which kind of phenotypic changes, are expected to be found in development.

Animals↗
PubMed1999

Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish.

The embryonic vertebrate heart is divided into two major chambers, an anterior ventricle and a posterior atrium. Although the fundamental differences between ventricular and atrial tissues are well documented, it is not known when and how cardiac anterior-posterior (A-P) patterning occurs. The expression patterns of two zebrafish cardiac myosin genes, cardiac myosin light chain 2 (cmlc2) and ventricular myosin heavy chain (vmhc), allow us to distinguish two populations of myocardial precursors at an early stage, well before the heart tube forms. These myocardial subpopulations, which may represent the ventricular and atrial precursors, are organized in a medial-lateral pattern within the precardiac mesoderm. Our examinations of cmlc2 and vmhc expression throughout the process of heart tube assembly indicate the important role of an intermediate structure, the cardiac cone, in the conversion of this early medial-lateral pattern into the A-P pattern of the heart tube. To gain insight into the genetic regulation of heart tube assembly and patterning, we examine cmlc2 and vmhc expression in several zebrafish mutants. Analyses of mutations that cause cardia bifida demonstrate that the achievement of a proper cardiac A-P pattern does not depend upon cardiac fusion. On the other hand, cardiac fusion does not ensure the proper A-P orientation of the ventricle and atrium, as demonstrated by the heart and soul mutation, which blocks cardiac cone morphogenesis. Finally, the pandora mutation interferes with the establishment of the early medial-lateral myocardial pattern. Altogether, these data suggest new models for the mechanisms that regulate the formation of a patterned heart tube and provide an important framework for future analyses of zebrafish mutants with defects in this process.

Animals↗
PubMed2002

Heads or tails? Amphioxus and the evolution of anterior-posterior patterning in deuterostomes.

In Xenopus, the canonical Wnt-signaling pathway acting through beta-catenin functions both in establishing the dorso-ventral axis and in patterning the anterior-posterior axis. This pathway also acts in patterning the animal-vegetal axis in sea urchins. However, because sea urchin development is typically indirect, and adult sea urchins have pentamerous symmetry and lack a longitudinal nerve cord, it has not been clear how the roles of the canonical Wnt-signaling pathway in axial patterning in sea urchins and vertebrates are evolutionarily related. The developmental expression patterns of Notch, brachyury, caudal, and eight Wnt genes have now been determined for the invertebrate chordate Amphioxus, which, like sea urchins, has an early embryo that gastrulates by invagination, but like vertebrates, has a later embryo with a dorsal hollow nerve cord that elongates posteriorly from a tail bud. Comparisons of Amphioxus with other deuterostomes suggest that patterning of the ancestral deuterostome embryo along its anterior-posterior axis during the late blastula and subsequent stages involved a posterior signaling center including Wnts, Notch, and transcription factors such as brachyury and caudal. In tunicate embryos, in which cell numbers are reduced and cell fates largely determined during cleavage stages, only vestiges of this signaling center are still apparent; these include localization of Wnt-5 mRNA to the posterior cytoplasm shortly after fertilization and localization of beta-catenin to vegetal nuclei during cleavage stages. Neither in tunicates nor in Amphioxus is there any evidence that the canonical Wnt-signaling pathway functions in establishment of the dorso-ventral axis. Thus, roles for Wnt-signaling in dorso-ventral patterning of embryos may be a vertebrate innovation that arose in connection with the evolution of yolky eggs and gastrulation by extensive involution.

Animals↗
PubMed2002

Transcriptional integration of competence modulated by mutual repression generates cell-type specificity within the cardiogenic mesoderm.

The way in which spatially patterned cellular identities are generated is a central question of organogenesis. In the case of Drosophila heart formation, the cardiac progenitors are specified in precise mesodermal positions, giving rise to multiple cell types in a highly ordered arrangement. Here, we study the mechanisms by which positional information conveyed by signaling pathways and a combinatorial code of activating and repressing transcription factors work together to confine the expression of the homeobox gene even-skipped (eve) to a small region of the dorsal mesoderm. By manipulating both expression patterns and binding sites for transcription factors, we show that a complex combination of regulatory activities converge on a single enhancer of eve to generate precisely targeted gene expression within the cardiac mesoderm. In particular, ladybird early (lbe), a homeobox gene expressed adjacent to eve, restricts the positive actions of factors downstream of wingless, decapentaplegic, and ras to generate the eve pattern. Mutation of a Lbe binding site causes dramatic expansion of expression and abolishes the responsiveness to repression by lbe. Conversely, eliminating eve in the mesoderm expands lbe expression into the normal eve-expressing territory, suggesting that mutual repression between eve and lbe is essential for delineating the spatial patterns of gene expression that specify cell types within the cardiac mesoderm.

Animals↗
PubMed2005

Establishing and maintaining axial growth: wall mechanical properties and the cytoskeleton.

Organ morphology depends on cell placement and directional cell expansion. Microtubules are involved in both of these processes so genetic approaches to understand the role microtubules play in organ expansion are not straightforward. Our use of the temperature-sensitive mor1-1 mutants led to the surprising discovery that Arabidopsis thaliana (L.) Heynh. root cells can establish and maintain transverse cellulose texture without well organized microtubule arrays. This work also demonstrated that cells can lose the ability to expand anisotropically without losing transversely oriented cellulose microfibrils. We suggest that microtubule disruption affects the cell's ability to generate long cellulose microfibrils, which may be essential for achieving growth anisotropy. Thus organ shape may depend not only on the orientation but also on the relative length of cellulose microfibrils during axis establishment and growth. More recent work has shown an important correlation between microtubule organization and the deposition patterns of the glycosylphosphatidylinositol (GPI)-anchored wall protein COBRA. Loss of microtubule organization is associated with the dissipation of transverse banding patterns of COBRA, suggesting that COBRA's function in maintaining anisotropic expansion may be microtubule-dependent.

Anisotropy↗
PubMed2004

The canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation.

The Wnt signaling pathway plays essential roles in embryogenesis of higher eukaryotes from diploblastic, radially symmetrical cnidarians to mice and humans. Whereas studies in model organisms such as Drosophila and Xenopus continue to elucidate how the Wnt pathway is regulated, studies of mouse mutants and cultured mammalian cells start to reveal how the Wnt pathway controls development and differentiation in mammals. Here we review some of the recent progresses in our understanding of the Wnt pathway. We focus on how this pathway, through regulating transcription of its downstream target genes, specifies pattern formation during mammalian embryogenesis and functions in the differentiation and maintenance of stem cells both in vivo and in vitro.

Animals↗
PubMed2004

Coordinate regulation of neural tube patterning and proliferation by TGFbeta and WNT activity.

Pattern formation and growth must be tightly coupled during embryonic development. In vertebrates, however, little is known of the molecules that serve to link these two processes. Here we show that bone morphogenetic proteins (BMP) coordinate the acquisition of pattern information and the stimulation of proliferation in the embryonic spinal neural tube. We have blocked BMP and transforming growth factor-beta superfamily (TGFbeta) function in the chick embryo using Noggin, a BMP antagonist, and siRNA against Smad4. We show that BMPs/TGFbetas are necessary to regulate pattern formation and the specification of neural progenitor populations in the dorsal neural tube. BMPs also serve to establish discrete expression domains of Wnt ligands, receptors, and antagonists along the dorsal-ventral axis of the neural tube. Using the extracellular domain of Frizzled 8 to block Wnt signaling and Wnt3a ligand misexpression to activate WNT signaling, we demonstrate that the Wnt pathway acts mitogenically to expand the populations of neuronal progenitor cells specified by BMP. Thus, BMPs, acting through WNTs, couple patterning and growth to generate dorsal neuronal fates in the appropriate proportions within the neural tube.

Animals↗
PubMed2005

Regulatory gene expressions in the ascidian ventral sensory vesicle: evolutionary relationships with the vertebrate hypothalamus.

In extant chordates, the overall patterning along the anteroposterior and dorsoventral axes of the neural tube is remarkably conserved. It has thus been proposed that four domains corresponding to the vertebrate presumptive forebrain, midbrain-hindbrain transition, hindbrain, and spinal cord were already present in the common chordate ancestor. To obtain insights on the evolution of the patterning of the anterior neural tube, we performed a study aimed at characterizing the expression of regulatory genes in the sensory vesicle of Ciona intestinalis, the anteriormost part of the central nervous system (CNS) related to the vertebrate forebrain, at tailbud stages. Selected genes encoded primarily for homologues of transcription factors involved in vertebrate forebrain patterning. Seven of these genes were expressed in the ventral sensory vesicle. A prominent feature of these ascidian genes is their restricted and complementary domains of expression at tailbud stages. These patterning markers thus refine the map of the developing sensory vesicle. Furthermore, they allow us to propose that a large part of the ventral and lateral sensory vesicle consists in a patterning domain corresponding to the vertebrate presumptive hypothalamus.

Animals↗
PubMed1998

Relationship between glycosylated hemoglobin, blood pressure, serum lipid profiles and body fat distribution in healthy Chinese.

Obesity-related metabolic disorders have not been adequately addressed due to a failure to distinguish the importance of general obesity or body fat distribution in relation to atherosclerotic risk factors, especially in the less obese populations. To assess the relationship between general obesity (reflected by BMI, total body fat percentage and total adiposity), body fat distribution (reflected by WHR, default regions and ROIs of DEXA) and atherosclerotic risk factors in the Chinese population, a total of 872 healthy subjects (477 male and 395 female) were enrolled in the study. The results indicated that the android pattern of fat distribution, independent of general obesity, was positively correlated with blood pressure, atherogenic indices, fasting and OGTT 2-h plasma glucose, glycosylated hemoglobin (HbA1c), serum concentration of cholesterol, triglyceride, LDL cholesterol and negatively correlated with HDL cholesterol in both genders. The gender differences in patterns of body fat distribution and atherosclerotic risk factors remained significant after adjustments were made for age, BMI and total adiposity, although diminished after further adjustments for body fat distribution. In conclusion, body fat distribution, rather than general obesity, is more correlated with obesity-related atherosclerotic risk factors and sex-associated differences. ROIs measured by DEXA may be a useful method to evaluate sex-associated changes in body fat distribution and atherosclerotic risk factors in the healthy Chinese population.

Adipose Tissue↗
PubMed2002

Altered whisker patterns induced by ectopic expression of Shh are topographically represented by barrels.

Barrels in the somatosensory cortex are segregated columns, which somatotopically relate to facial whiskers. The barrel pattern is assumed to be determined by an extrinsic mechanism (the domino theory). This theory is based on whisker lesion experiments and developmental observations regarding the serial establishment of the somatotopic pattern in which pattern formations are relayed from the periphery to the central nervous system. However, the barrel pattern is possibly determined by an intrinsic mechanism, especially in its primitive form. In order to investigate the definitive mechanism, we established an experimental system in which the cortical barrel pattern can be altered, not by using a lesion paradigm, but by epigenetically changing the whisker pattern. Sonic hedgehog (Shh) plays a pivotal role in whisker development. We transfected an adenovirus harboring chicken Shh (Ad-cShh) to mouse embryos (E9.5-E11.5) using an in utero surgical technique. When Ad-cShh was expressed in the epidermis, Bmp4, Ptch, Ptch2 and Gli1 were induced ectopically in the interfollicular region. In contrast, the expression of Bmp2 and Shh itself was unaltered. At a suitable dose of Ad-cShh, some pups displayed supernumerary whiskers or a disordered whisker pattern. The barrel patterns of these mice after the critical period were topographic representations of the contralateral side of the new whisker patterns when visualized by a cytochrome oxidase or Nissle staining method, supporting the instructive role of the extrinsic mechanism.

Afferent Pathways↗
PubMed2002

Pattern formation: swimming in retinoic acid.

The metabolite retinoic acid has been implicated as a key player during anterior-posterior patterning in vertebrate embryos. Recent studies in zebrafish extend this model by demonstrating the influence of retinoic acid on endoderm regionalization.

Animals↗
PubMed2004

Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis.

Somites, the segmented building blocks of the vertebrate embryo, arise one by one in a patterning process that passes wavelike along the anteroposterior axis of the presomitic mesoderm (PSM). We have studied this process in Xenopus embryos by analyzing the expression of the bHLH gene, Thylacine1, which is turned on in the PSM as cells mature and segment, in a pattern that marks both segment boundaries and polarity. Here, we show that this segmental gene expression involves a PSM enhancer that is regulated by retinoic acid (RA) signaling at two levels. RA activates Thylacine1 expression in rostral PSM directly. RA also activates Thylacine1 expression in the caudal PSM indirectly by inducing the expression of MKP3, an inhibitor of the FGF signaling pathway. RA signaling is therefore a major contributor to segmental patterning by promoting anterior segmental polarity and by interacting with the FGF signaling pathway to position segmental boundaries.

Animals↗
PubMed2001

Role for sperm in spatial patterning of the early mouse embryo.

Despite an apparent lack of determinants that specify cell fate, spatial patterning of the mouse embryo is evident early in development. The axis of the post-implantation egg cylinder can be traced back to organization of the pre-implantation blastocyst. This in turn reflects the organization of the cleavage-stage embryo and the animal-vegetal axis of the zygote. These findings suggest that the cleavage pattern of normal development may be involved in specifying the future embryonic axis; however, how and when this pattern becomes established is unclear. In many animal eggs, the sperm entry position provides a cue for embryonic patterning, but until now no such role has been found in mammals. Here we show that the sperm entry position predicts the plane of initial cleavage of the mouse egg and can define embryonic and abembryonic halves of the future blastocyst. In addition, the cell inheriting the sperm entry position acquires a division advantage and tends to cleave ahead of its sister. As cell identity reflects the timing of the early cleavages, these events together shape the blastocyst whose organization will become translated into axial patterning after implantation. We present a model for axial development that accommodates these findings with the regulative nature of mouse embryos.

Animals↗
PubMed2000

Plzf regulates limb and axial skeletal patterning.

The promyelocytic leukaemia zinc finger (Plzf) protein (encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here we generate Zfp145-/- mice and show that Plzf is essential for patterning of the limb and axial skeleton. Plzf inactivation results in patterning defects affecting all skeletal structures of the limb, including homeotic transformations of anterior skeletal elements into posterior structures. We demonstrate that Plzf acts as a growth-inhibitory and pro-apoptotic factor in the limb bud. The expression of members of the abdominal b (Abdb) Hox gene complex, as well as genes encoding bone morphogenetic proteins (Bmps), is altered in the developing limb of Zfp145-/- mice. Plzf regulates the expression of these genes in the absence of aberrant polarizing activity and independently of known patterning genes. Zfp145-/- mice also exhibit anterior-directed homeotic transformation throughout the axial skeleton with associated alterations in Hox gene expression. Plzf is therefore a mediator of anterior-to-posterior (AP) patterning in both the axial and appendicular skeleton and acts as a regulator of Hox gene expression.

Animals↗
PubMed1998

Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.

The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation nail patella syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.

Amino Acid Sequence↗
PubMed2002

Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: factors influencing the outcome.

OBJECTIVE: The management of children with congenital adrenal hyperplasia (CAH) remains a challenge, especially with regard to growth potentials. The objective of our analysis was to uncover the factors that influence the growth and final height of patients with CAH. DESIGN: The linear growth pattern and body mass index (BMI) at different developmental stages (birth to 2 years, 2 years to puberty initiation and puberty initiation to final height) and the final height achieved were analysed retrospectively in 48 patients with 21-hydroxylase deficiency; 17 with the salt-wasting (SW) form, 25 with the simple virilizing (SV) and six with the nonclassical (NC) form. RESULTS: Mean final height (FH) and FH-SDS were, respectively, 170.8 +/- 5.6 m and -0.57 +/- 0.8 in males and 156.7 +/- 6 cm and -0.61 +/- 1 in females with the SW form, 166.1 +/- 6.1 cm and -1.05 +/- 1 in males and 151.6 +/- 5.4 cm and -1.4 +/- 1 in females with the SV form and 159.7 +/- 6.9 cm and 0.3 +/- 1.4 in females with the NC form. In subjects with the SW form, height SDS at 2 years, at puberty initiation and at FH were -0.18 +/- 0.9, 0.11 +/- 1.28 and -0.6 +/- 1.0, respectively. FH achieved was not different from target height (TH) in the SW group, but it was significantly lower than TH in the SV group (P = 0.003). FH in the SW group showed a positive correlation to the height achieved at 2 years of age (r = 0.68, P = 0.019), and height at 2 years was negatively related to the hydrocortisone dose in the birth to 2-year period (r = -0.79, P = 0.011). FH showed no correlation to hydrocortisone dose at any of the three developmental periods studied. BMI-SDS were not different in the various forms of CAH and showed no correlation to FH or hydrocortisone dose. Age at menarche was comparable to that in our general population. CONCLUSIONS: Under our conditions of management, the final height of patients with the salt-wasting form was comparable to the target height and to the most favourable literature data. The patients with the simple virilizing form fare less well, mainly due to delayed diagnosis and consequent advancement of bone age and early puberty. In salt-wasting patients, height at 2 years is comparable to normals, it is influenced by the hydrocortisone dose and is related to the final height. Some height is lost during puberty. Hence, monitoring treatment over the first 2 years and during puberty is critical for the outcome in these patients.

Adolescent↗