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.2008 Apr 22;94(1):90-104.
doi: 10.1016/j.physbeh.2007.11.024. Epub 2007 Nov 22.

Factors regulating vagal sensory development: potential role in obesities of developmental origin

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Factors regulating vagal sensory development: potential role in obesities of developmental origin

Edward A Fox et al. Physiol Behav..

Abstract

Contributors to increased obesity in children may include perinatal under- or overnutrition. Humans and rodents raised under these conditions develop obesity, which like obesities of other etiologies has been associated with increased meal size. Since vagal sensory innervation of the gastrointestinal (GI) tract transmits satiation signals that regulate meal size, one mechanism through which abnormal perinatal nutrition could increase meal size is by altering vagal development, possibly by causing changes in the expression of factors that control it. Therefore, we have begun to characterize development of vagal innervation of the GI tract and the expression patterns and functions of the genes involved in this process. Important events in development of mouse vagal GI innervation occurred between midgestation and the second postnatal week, suggesting they could be vulnerable to effects of abnormal nutrition pre- or postnatally. One gene investigated was brain- derived neurotrophic factor (BDNF), which regulates survival of a subpopulation of vagal sensory neurons. BDNF was expressed in some developing stomach wall tissues innervated by vagal afferents. At birth, mice deficient in BDNF exhibited a 50% reduction of putative intraganglionic laminar ending mechanoreceptor precursors, and a 50% increase in axons that had exited fiber bundles. Additionally, BDNF was required for patterning of individual axons and fiber bundles in the antrum and differentiation of intramuscular array mechanoreceptors in the forestomach. It will be important to determine whether abnormal perinatal environments alter development of vagal sensory innervation of the GI tract, involving effects on expression of BDNF, or other factors regulating vagal development.

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Figures

Fig. 1
Fig. 1
Confocal images illustrating three stages of development of vagal axons and fiber bundles in the forestomach.A. At E13.5 a plexus-like pattern started to emerge consisting of separate axons and axon bundles of small diameter.B. At E14.5, axon bundle diameters and distances between separate axons and axon bundles increased.C. By E16.5, these diameters and distances increased further, and the pattern of organization of axon bundles and separate axons was similar to that observed at mature ages. Scale bars = 10 µm.
Fig. 2
Fig. 2
Confocal images of DiI-labeled putative IGLE precursors shown in three stages of development in the forestomach.A. An early stage of putative IGLE precursor shown at P0, which consisted of DiI-labeled vagal fibers and axons in the myenteric plexus, terminating in growth cone-like puncta structures (arrow) present at the surface of myenteric ganglia.B. A second stage of putative IGLE precursor maturation observed here at P3 with increased numbers of putative terminal puncta, which in this instance consisted predominantly of small quasi-spherical structures (arrow).C. A third stage of putative IGLE precursor maturation shown here at P8 with continued development of putative terminals, consisting of more numerous terminal structures that were more densely packed in leaf-like patterns arranged in several groups. This and other IGLEs at this stage often exhibited some groups of terminal puncta lying below the plane of the myenteric plexus, and others above it. Scale bars = 10 µm.
Fig. 3
Fig. 3
Confocal images of DiI-labeled putative IMA precursors shown in four stages of development in the muscle layers of the forestomach.A. An early stage of putative IMA precursor development illustrated here at P0. An axon exited the myenteric plexus and entered the smooth muscle layer before branching into two processes that could have been growing axons, or precursors of IMA telodendria (arrows). A small neurite that extended from the termination of one of these processes (arrowhead) may have represented the initial formation of an additional putative telodendrion. Separate axons present were in the myenteric plexus.B. At the next stage of putative IMA precursor development also illustrated here at P0, single axons exited the myenteric plexus and entered the muscle layer, distributed additional axons and short rectilinear fibers forming precursors of IMA telodendria (e.g., arrows) that paralleled the muscle fibers, and also exhibited an interconnecting crossbridge fiber (arrowhead).C. Putative IMA precursor at P3 in the muscle layer at a later stage of maturation in which the telodendria (running diagonally from upper right to lower left) had lengthened and become more numerous - as had crossbridge fibers (arrowheads).D. Montage of confocal images of putative IMA precursors at P4 demonstrating the further lengthening of their maturing telodendria relative to earlier stages illustrated in panels A–C, and representing a portion of a field of multiple IMAs that was forming. Scale bars = 10 µm.
Fig. 4
Fig. 4
Brightfield photomicrographs of sections from BDNFLacZ mice stained with X-gal illustrating BDNF expression in the stomach wall at E17.5. The images in panels A and C were counterstained with neutral red, illustrating all tissue layers of the stomach wall as well as X-gal staining, whereas B and D respectively are nearby sections that were stained only with X-gal to illustrate the extent of BDNF expression.A,B. BDNF expression occurred in tissues that developed into the lamina propria of the mucosa in the antrum and corpus. It was also present in arterial blood vessel walls (cross-sectioned in this sample) within the muscle wall and adjacent portion of the submucosa. Scale bar in A = 50 µm, also applies to B,C and D.C,D. BDNF expression was also present in some regions of tissues developing into both layers of the antrum smooth muscle wall. Additionally, near the center of the image in D there is an artery running on the surface of the stomach wall that exhibited BDNF expression and a branch of this vessel that entered the stomach wall and continued to express BDNF is present in the lower left of the image. Lamina propria, lp; smooth muscle, sm.
Fig. 5
Fig. 5
Preliminary quantitative comparisons of the effects of BDNF +/+, +/− and −/− genotypes on vagal innervation of the stomach at P0.A. Mean total numbers of vagal bundles counted at all sampling sites.B. Mean total numbers of intersections of separate vagal axons with the lines of the counting grid added across all sampling sites.C. Mean total numbers of putative IGLE precursors counted at all sampling sites.D. Mean total numbers of intersections of telodendria of putative IMA precursors with counting grid lines added across all sampling sites. * Significantly different from wild type at p < 0.5 level.
Fig. 6
Fig. 6
Confocal images of DiI-labeled vagal fibers and terminals compared in P0 BDNF knockout (−/−) and wild-type (+/+) mice.A. Putative IMA precursors present in the forestomach of BDNF +/+ mice with telodendria extending horizontally across the image.B. The growth of some of the telodendria (oriented diagonally across the image) of putative IMA precursors observed in the forestomach of BDNF −/− mice appeared stunted and they had larger-than-normal diameters.C. In the antrum of BDNF +/+ mice separate axons and axon bundles typically formed adult-like patterns of vagal stomach wall innervation as illustrated in this image.D. In contrast, in the antrum of BDNF −/− mice, separate vagal axons and fiber bundles often exhibited a disorganized pattern of innervation. The example shown here is an extreme instance, demonstrating both aberrant organization as well as a large increase in axon density. Scale bars = 10 µm.
Fig. 7
Fig. 7
The temporal relationships between developmental age, BDNF expression in the stomach, and stages of vagal development are represented. These relationships illustrate the possibility for abnormal perinatal nutritional or hormonal environments to modify ongoing BDNF expression and thereby its regulation of vagal sensory development, involving vagal axon development at earlier ages and differentiation and growth of sensory receptors at later ages.
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