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Risk factors for coronary heart disease among Navajo Indians: findings from the Navajo Health and Nutrition Survey.

Coronary heart disease was uncommon among the Navajo in the past, but appears to have increased substantially over the last few decades. The 1991-1992 Navajo Health and Nutrition Survey, which included interviews and examinations of 303 men and 485 women between the ages of 20 and 91 y, is the first population-based examination of coronary heart disease risk factors in this tribe. Coronary heart disease risk characteristics were common, particularly overweight (men, 35%; women, 62%), hypertension (men, 23%; women, 14%) and diabetes mellitus (men, 17%; women, 25%). Among 20- to 39-y-olds, a large proportion of men reported that they currently smoked cigarettes (23%); use of chewing tobacco or snuff was also prevalent among these 20- to 39-y-old men (37%) and women (31%). Although serum concentrations of total cholesterol were fairly comparable to those seen in the general U.S. population, fasting serum triglyceride concentrations were high (median: men, 132 mg/dL; women, 137 mg/dL), and concentrations of HDL cholesterol were low, particularly among women (median: men, 42 mg/dL; women, 44 mg/dL). Body mass index was associated with levels of most risk factors, and, independently of the level of overweight, a truncal pattern of body fat was related to adverse lipid levels among men. A large proportion of men (20%) and women (30%) reported not having participated in physical activity during the preceding month. Lessons learned from past intervention activities among the Navajo, particularly those for diabetes, may be useful in managing these risk factors to reduce the future burden of coronary heart disease.

Adolescent↗

Failure to maintain eye-specific segregation in nob, a mutant with abnormally patterned retinal activity.

Axon terminals from the two eyes initially overlap in the dorsal-lateral geniculate nucleus (dLGN) but subsequently refine to occupy nonoverlapping territories. Retinal activity is required to establish and maintain this segregation. We show that despite the presence of retinal activity, segregated projections desegregate when the structure of activity is altered. Early in development, spontaneous retinal activity in the no b-wave (nob) mouse is indistinguishable from that of wild-type mice, and eye-specific segregation proceeds normally. But, around eye-opening, spontaneous and visually evoked activity in nob retinas become abnormal, coincident with a failure to preserve precise eye-specific territories. Dark-rearing studies suggest that altered visual experience is not responsible. Transgenic rescue of the mutated protein (nyctalopin) within nob retinal interneurons, without rescuing expression in either retinal projection neurons or their postsynaptic targets in the dLGN, restores spontaneous retinal activity patterns and prevents desegregation. Thus, normally structured spontaneous retinal activity stabilizes newly refined retinogeniculate circuitry.

Animals↗

Patterning the pharyngeal arches.

The presence of a muscularised pharynx with skeletal support is a fundamental vertebrate characteristic. Developmentally, the pharynx arises from the pharyngeal arches on either side of the head of vertebrate embryos. The development of the pharyngeal arches is complex involving a number of disparate embryonic populations, ectoderm, endoderm, neural crest and mesoderm, which must be co-ordinated to generate the components and overall identity of each of the arches. Previous studies suggested that it is the neural crest that plays a pivotal role in patterning the pharyngeal arches. It is now also becoming clear, however, that there are crest-independent patterning mechanisms. Therefore, pharyngeal arch patterning is more complex than was previously believed and there must be an integration of crest-dependent and -independent patterning mechanisms. BioEssays 23:54-61, 2001.

Animals↗

Zebrafish admp is required to restrict the size of the organizer and to promote posterior and ventral development.

Bone morphogenetic proteins (Bmps) and their roles during early dorsoventral patterning of the vertebrate embryo are well understood. The role and regulation of a more distant member of this family, the anti-dorsalizing morphogenetic protein (Admp), however, are less clear. Here, we report the isolation and characterization of zebrafish admp. Unlike other bmps, admp is exclusively expressed on the dorsal side. Expression starts at blastula stages in the region of the organizer, giving rise to anterior neuroectoderm and axial mesoderm. During the course of gastrulation, both the neuroectodermal and the mesodermal admp transcripts vanish in an anterior-posterior wave. The maintenance of admp expression is positively influenced by Nodal signaling and by Bozozok (Boz), an organizer-promoting homeodomain protein acting as a repressor of early bmp2b expression. Despite the positive effect of boz on admp expression, Boz and Admp have rather opposite effects on zebrafish patterning, as revealed in gain- and loss-of-function experiments. Upon overexpression, admp has Bmp-like activities causing a smaller organizer and enhanced ventral specification, very similar to the phenotype caused by the loss of boz function in mutant embryos. Antisense-based admp knockdown, on the other side, leads to an enlarged organizer and impaired ventral and posterior development, as observed in embryos after boz overexpression. This finding indicates that admp is required for the development of embryonic structures normally suppressed by organizer activities. The seeming discrepancy between the regulative and functional relationship of boz and admp is discussed, and models are proposed according to which Admp might be part of a negative feedback loop to pattern and confine the organizer region.

Animals↗

Pattern formation in the zebrafish retina.

During the past 15 years, the zebrafish has become established as a genetic model organism to study vertebrate development. It is particularly well suited for the analysis of the retina, and several genetic screens have yielded a large number of mutants affecting retinal development. Most of these mutants still await thorough analysis and molecular characterization, but work on a handful of genes has already generated interesting results that shed some light on patterning mechanisms employed in the vertebrate retina.

Animals↗

Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain.

Glypicans are essential modulators of cell signalling during embryogenesis. Little is known about their functions in brain development. We show here that mouse glypicans (gpc-1 to gpc-6) are differentially expressed in embryonic brains during key morphogenetic events. In gastrulating embryos, gpc-4 is the only glypican expressed in anterior visceral endoderm. During neural tube closure, gpc-4 transcripts are restricted to the anterior neural ridge and telencephalon. At this stage, gpc-1 expression shifts from trunk and head mesenchyme to neural tube. Gpc-3 mRNA appears across the ventral neural tube, then in the lamina terminalis and hypothalamus. Gpc-2 and gpc-6 transcripts are in all brain compartments. Gpc-5 is found in ventral brains as neurogenesis starts. Onset of neurogenesis also coincides with differential expression of glypican genes either in neural progenitors or in differentiating neurons. The novel expression sites of glypicans shown here contribute to the identification of signalling molecules involved in brain patterning.

Animals↗

Arthropod segmentation: why centipedes are odd.

Recent work has revealed a double segmental periodicity of gene expression in the centipede, a potential molecular explanation for the observation that this arthropod always has an odd number of trunk segments. Is this an oddity of centipedes, or might it mean that double segmental pair-rule patterning dates back to the Ur-arthropod?

Animals↗

Regionalised signalling within the extraembryonic ectoderm regulates anterior visceral endoderm positioning in the mouse embryo.

The development of the anterior-posterior (AP) axis in the mammalian embryo is controlled by interactions between embryonic and extraembryonic tissues. It is well established that one of these extraembryonic tissues, the anterior visceral endoderm (AVE), can repress posterior cell fate and that signalling from the other, the extraembryonic ectoderm (ExE), is required for posterior patterning. Here, we show that signals from the prospective posterior ExE repress AVE gene expression and affect the distribution of the AVE cells. Surgical ablation of the prospective posterior, but not the anterior, extraembryonic region at 5.5 days of development (E5.5) perturbs the characteristic distal-to-anterior distribution of AVE cells and leads to a dramatic expansion of the AVE domain. Time-lapse imaging studies show that this increase is due to the ectopic expression of an AVE marker, which results in a symmetrical positioning of the AVE. Surgical ablation of this same ExE region after the distal-to-anterior migration has already commenced, at E5.75, does not affect the localisation of the AVE, indicating that this effect takes place within a short time window. Conversely, transplanting the prospective posterior, but not the anterior, extraembryonic region onto isolated E5.5 embryonic explants drastically reduces the AVE domain. Further, transplantation experiments demonstrate that the signalling regulating AVE gene expression originates from the posterior ExE, rather than its surrounding VE. Together, our results show that signals emanating from the future posterior ExE within a temporal window both restrict the AVE domain and promote its specific positioning. This indicates for the first time that the ExE is already regionalised a day before the onset of gastrulation in order to correctly set the orientation of the AP axis of the mouse embryo. We propose a reciprocal function of the posterior ExE and the AVE in establishing a balance between the antagonistic activities of these two tissues, essential for AP patterning.

Animals↗

Signals derived from the underlying mesoderm are dispensable for zebrafish neural crest induction.

Signals from the non-neural ectoderm, the neural ectoderm, and the underlying mesoderm have all been implicated in the induction of neural crest. Bone morphogenetic protein (BMP) signaling in particular has an important role in this process; however, it is unclear whether this activity of BMP is due to its effects on patterning the underlying mesoderm, to its ability to establish a competent neural plate boundary zone, or to the direct specification of neural crest at intermediate levels of activity within a BMP gradient. We show neural crest induction occurs in zebrafish in the absence of involuted mesoderm, indicating that this tissue and signals derived from it are dispensable for the formation of neural crest. Dorsal-involuted mesoderm is a major source of secreted BMP antagonists, and the activity of BMP signaling is thought to depend on the presence of the opposing activity of these antagonists. We find that the three BMP antagonists known to be expressed during gastrulation in zebrafish, noggin1, follistatin, and chordin, are dispensable for neural crest induction. These results suggest that mechanisms for restricting the spatio-temporal pattern of BMP expression may compensate for the loss of secreted BMP antagonist activity in establishing dorso-ventral patterning, neural induction, and the neural crest.

Animals↗

Rho1 regulates signaling events required for proper Drosophila embryonic development.

The Rho small GTPase has been implicated in many cellular processes, including actin cytoskeletal regulation and transcriptional activation. The molecular mechanisms underlying Rho function in many of these processes are not yet clear. Here we report that in Drosophila, reduction of maternal Rho1 compromises signaling pathways consistent with defects in membrane trafficking events. These mutants fail to maintain expression of the segment polarity genes engrailed (en), wingless (wg), and hedgehog (hh), contributing to a segmentation phenotype. Formation of the Wg protein gradient involves the internalization of Wg into vesicles. The number of these Wg-containing vesicles is reduced in maternal Rho1 mutants, suggesting a defect in endocytosis. Consistent with this, stripes of cytoplasmic beta-catenin that accumulate in response to Wg signaling are narrower in these mutants relative to wild type. Additionally, the amount of extracellular Wg protein is reduced in maternal Rho1 mutants, indicating a defect in secretion. Signaling pathways downregulated by endocytosis, such as the epidermal growth factor receptor (EGFR) and Torso pathways, are hyperactivated in maternal Rho1 mutants, consistent with a general role for Rho1 in regulating signaling events governing proper patterning during Drosophila development.

Animals↗

Temporally dynamic response to Wingless directs the sequential elaboration of the proximodistal axis of the Drosophila wing.

The Drosophila wing imaginal disc gives rise to three main regions along the proximodistal axis of the dorsal mesothoracic segment: the notum, proximal wing, and wing blade. Development of the wing blade requires the Notch and wingless signalling pathways to activate vestigial at the dorsoventral boundary. However, in the proximal wing, Wingless activates a different subset of genes, e.g., homothorax. This raises the question of how the downstream response to Wingless signalling differentiates between proximal and distal fate specification. Here, we show that a temporally dynamic response to Wingless signalling sequentially elaborates the proximodistal axis. In the second instar, Wingless activates genes involved in proximal wing development; later in the third instar, Wingless acts to direct the differentiation of the distal wing blade. The expression of a novel marker for proximal wing fate, zfh-2, is initially activated by Wingless throughout the "wing primordium," but later is repressed by the activity of Vestigial and Nubbin, which together define a more distal domain. Thus, activation of a distal developmental program is antagonistic to previously established proximal fate. In addition, Wingless is required early to establish proximal fate, but later when Wingless activates distal differentiation, development of proximal fate becomes independent of Wingless signalling. Since P-element insertions in the zfh-2 gene result in a revertable proximal wing deletion phenotype, it appears that zfh-2 activity is required for correct proximal wing development. Our data are consistent with a model in which Wingless first establishes a proximal appendage fate over notum, then the downstream response changes to direct the differentiation of a more distal fate over proximal. Thus, the proximodistal domains are patterned in sequence and show a distal dominance.

Animals↗

Xwnt-2 (Xwnt-2b) is maternally expressed in Xenopus oocytes and embryos.

Xwnt-2 (formerly Xwnt-2b) is a member of the Xwnt-8 class of axis-inducing Wnts. Its zygotic expression is at the prosencephalic-mesencephalic border of the early tadpole brain and above the heart primordium [Mech. Dev. 63 (1997) 199]. Here, we report that Xwnt-2 has an earlier, maternal pattern of expression. It is detected in the oocyte, egg and the developing embryo. Studies of the spatial localization of maternal Xwnt-2 show transcripts in both vegetal and animal blastomeres with enrichment in the animal hemisphere. The identification of maternal Xwnt-2 raises questions about possible roles of dorsalizing Xwnts in axial patterning of the Xenopus embryo.

Animals↗

Anf: a novel class of vertebrate homeobox genes expressed at the anterior end of the main embryonic axis.

Five novel genes homologous to the homeobox-containing genes Xanf-1 and Xanf-2 of Xenopus and Hesx-1/Rpx of mouse have been identified as a result of a PCR survey of cDNA in sturgeon, zebrafish, newt, chicken and human. Comparative analysis of the homeodomain primary structure of these genes revealed that they belong to a novel class of homeobox genes, which we name Anf. All genes of this class investigated so far have similar patterns of expression during early embryogenesis, characterized by maximal transcript levels being present at the anterior extremity of the main embryonic body axis. The data obtained also suggest that, despite considerable high structural divergence between their homeodomains, all known Anf genes may be orthologues, and thus represent one of the most quickly evolving classes of vertebrate homeobox genes.

Amino Acid Sequence↗

Ventral mesoderm induction and patterning by bone morphogenetic protein heterodimers in Xenopus embryos.

Bone morphogenetic proteins (BMPs) perform diverse functions in vertebrate development. Here we demonstrate that the heterodimeric BMP-4/7 protein directly induces ventral mesoderm and blood in Xenopus animal caps, and BMP-2/7 heterodimers may function similarly. We also provide indirect evidence that BMP heterodimers function in embryos, using assays with dominant-negative BMP ligands. Homodimeric BMP-2 and BMP-4 proteins do not induce mesoderm, but they ventralize mesoderm induction by activin. In contrast, BMP-7 protein interferes with mesoderm induction by activin, but BMP-7 stimulates ventral mesoderm induction by the heterodimer, BMP-4/7. This novel property of BMP-7 distinguishes it from other BMPs. BMP-7 may therefore function in early embryogenesis to antagonize activin signals and potentiate BMP signals. We propose that BMP heterodimers convey signals for ventral mesoderm induction and patterning in Xenopus development.

Activins↗

Retinoid signalling and hindbrain patterning.

Retinoid signalling has been implicated in regulating a wide variety of processes in vertebrate development. Recent advances from analyses on the synthesis, degradation and distribution of retinoids in combination with functional analysis of signalling components have provided important insights into the regulation of patterning the nervous system and the hindbrain in particular.

Animals↗

Left-right development: the roles of nodal cilia.

Cilia on the ventral side of the mouse node have been implicated in initiating the left-right axis during embryonic development, but how cilia relate to other factors in the left-right pathway and the mechanism by which cilia convey patterning information remain uncertain.

Animals↗