Denervation of peripheral chemoreceptors decreases breathing movements in fetal sheep.

The role of the peripheral chemoreceptors in the control of fetal breathing movements has not been fully defined. To determine whether denervation of the peripheral chemoreceptors affects fetal breathing movements, we studied 14 chronically catheterized fetal sheep from 120 to 138 days of gestation. In seven fetuses the chemoreceptors were denervated by bilateral section of the vagus and carotid sinus nerves; in seven others, sham operations were performed. We compared several variables during two study periods: 0-5 and 6-13 days after operation. In the denervated fetuses there were significant decreases in the incidence and amplitude of fetal breathing movements during both study periods. There were no differences between the two groups in incidence of low-voltage electrocortical activity, arterial pH and blood gas tensions, fetal heart rate, mean arterial blood pressure, or duration of survival after operation or birth weight. We conclude that denervation of the peripheral chemoreceptors decreases fetal breathing movements. These results indicate that the peripheral chemoreceptors are active during fetal life and participate in the control of fetal breathing movements.

HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.

Solid tumors are frequently necrotic and hypoxic due to poor vascularization. Tumor cells adapt to hypoxia by modulating their phenotype. Key players in this process are the hypoxia-inducible factors (HIF-1alpha to 3alpha). HIFs are also expressed during normal development; for example, HIF-2alpha is specifically expressed and appears to be involved in the development of the murine sympathetic nervous system (SNS). Here, we demonstrate that HIF-2alpha protein is selectively present in human fetal week 8.5 SNS paraganglia. Neuroblastoma is derived from SNS precursors. In a subset of neuroblastomas, a spontaneous neuronal to neuroendocrine differentiation occurs in areas adjacent to necrotic zones. As HIF-2alpha activity has been associated not only with hypoxic but also with hypoglycemic conditions, we have investigated putative effects of hypoxia, glucose depletion, and HIF-2alpha on the neuroblastoma phenotype. HIF-2alpha was detected in hypoxic and in well-oxygenized neuroblastoma cells and tissue, presumably reflecting their embryonic features. With regard to differentiation, hypoxic cells lost their neuronal/neuroendocrine features and gained marker gene expression associated with an immature, neural crest-like phenotype. Low glucose potentiated the effect of hypoxia. These findings suggest that poorly vascularized neuroblastomas become immature and maintain a more aggressive phenotype, which possibly could involve a sustained stabilization and activation of HIF-2alpha.

Development of type I cells of the rabbit subclavian glomera (aortic bodies): a light, fluorescence and electron microscopic study.

The embryogenesis of the subclavian glomera (aortic bodies) is controversial. Past investigators have attributed the development of the Type I cells to mesodermal and/or neural elements. Based on the results of the present light microscopic, fluorescence histochemical and electron microscopic study of rabbit aortic bodies from 16 days of gestation (term:31 days) to four days postpartum, it appears that the Type I glomus cell are derived from cells of neural crest origin. The subclavian anlage is associated with cells of neural crest origin. The subclavian glomus anlage is associated with cells of vagal origin throughout its development. Evidence of Type I cell development from pre-existing mesodermal condensations is not observed. Type I cells exhibit formaldehyde-induced-fluorescence by the twentieth day of gestation. Dense-cored cytoplasmic vesicles are apparent by the sixteenth day of gestation. The number of cytoplasmic vesicles increases steadily, but the greatest increase of vesicles is observed between the twenty-eighth day of gestation and birth. Primitive Type I glomus cells exhibit abundant polysomes and rough endoplasmic reticulum indicative of synthetic activity. Nerve terminals are apparent adjacent to Type I cells by the twentieth day of gestation, but synaptogenesis does not occur until sometime between the twenty-fourth and twenty-eighth days of gestation. Abundant vascularity, characteristic of chemosensory glomera, is not achieved until the twenty-eighth day of gestation.

The neural crest: its relations with APUD and paraneuron concepts.

The neural crest cells give rise to a large variety of derivatives including neural, mesenchymal, APUD and/or paraneuron cell types. A better knowledge of these derivatives was partly achieved through studies using Le Douarin's quail/chick marker system. We review here evidences which were thus provided for a neural crest origin of calcitonin containing cells, carotid body, aortic paraganglia, adrenomedulla, and against a neurectodermal origin of enterogastric and respiratory tract endocrine cells. The role of neural crest cells in Pearse's APUD system is discussed. The results implicate that an explanation for the common properties of these cell types and their pathological and biochemical significance should not be looked for in a common embryological origin but at another level. The place of neural crest and, more generally, neurectoderm derivatives in the paraneuron concept of Fujita is examined. The relevance of the epithelial origin of these cell types to their "receptosecretory" function is stressed. Considering neural crest itself as a unique system is still questioned and discussed here. Its ubiquity and penetration of other systems is pointed out as a widespread phenomenon which is not restricted to APUD and paraneuron systems.

Immunohistochemical localization of WE-14 in the developing porcine sympathoadrenal cell lineage.

Immunohistochemical investigation of the post-translational processing of chromogranin A (CgA) to generate WE-14 in the sympathoadrenal cell lineage of the developing porcine fetus (F) detected intense CgA and weak WE-14 immunoreactivity in migrating neuroblast cells of the diffuse sympathetic ganglia adjacent to the dorsal aorta and projecting toward the cortical mass at F24-27. F37-42; WE-14 immunoreactivity was detected in chromaffinoblasts at the periphery of the developing cortex and at F54-56 days gestation WE-14 immunoreactivity was detected in a large population of central medullary cells. From F74 to F76 days and thereafter the number of cells exhibiting intense WE-14 immunostaining decreased, and the majority of chromaffin cells exhibited uniform weak WE-14 immunostaining. At postnatal day 1 (P1) intense WE-14 immunoreactivity was primarily confined to clusters of chromaffin cells with weak immunostaining in the general population. The transitory neuroblasts, chromaffinoblasts, and maturing chromaffin cell population exhibited uniform intense CgA immunostaining through gestation and after birth. Additional observations detected intense CgA and WE-14 immunostaining in extrachromaffin tissue at P1 and in neuronal-like cells in vessels of the aortic arch at F37. This study has demonstrated that CgA is post-translationally processed to generate WE-14 during early fetal development in the migrating progenitor cells of the porcine sympathoadrenal lineage.

Immunohistochemical characteristics of human paraganglion cells and sensory corpuscles associated with the urinary bladder. A developmental study in the male fetus, neonate and infant.

Triple label immunohistochemistry was used to study the coexistence of the catecholamine-synthesising enzymes dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) and several neuropeptides including neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM) and galanin (GAL) as well as nitric oxide synthase (NOS) in developing pelvic paraganglion cells in a series of human male fetal, neonatal and infant specimens ranging in age from 13 wk of gestation to 3 y postnatal. 13-20 wk old fetal specimens possessed large clusters of paraganglion cells lying lateral to the urinary bladder and prostate gland which were intensely DBH-immunoreactive (-IR) but lacked TH, NOS and the neuropeptides investigated. With increasing fetal age small clusters of paraganglion cells were observed in the muscle coat of the urinary bladder. At 23 wk of gestation occasional paraganglion cells were NOS or NPY-IR while at 26 wk of gestation the majority of paraganglion cells were TH-IR and a few were SOM or GAL-IR. Some postnatal paraganglia within the bladder musculature contained cells which were all VIP, SP or CGRP-IR while others displayed coexistence of NOS and NPY, SP and CGRP, or NPY and VIP. The presence of NOS in certain paraganglion cells indicates their capacity to generate nitric oxide (NO). These results show that human paraganglion cells develop different phenotypes possibly dependent upon their location within the bladder wall. A delicate plexus of branching varicose nerves was observed in the fetal paraganglia which increased in density with increasing gestational age. The majority of these nerves were VIP-IR while others were CGRP, SP, NPY, NOS or GAL-IR. The presence of nerve terminals adjacent to the paraganglion cells implies a neural influence on the functional activity of the paraganglia. Some paraganglia in the late fetal and early postnatal specimens contained Timofeew's sensory corpuscles, resembling pacinian corpuscles in their morphology. The central nerve fibre of these corpuscles displayed immunoreactivity for SP, CGRP and NOS, the latter indicating a possible role for NO in afferent transmission from the urinary bladder. In addition, a few corpuscles were penetrated by a noradrenergic nerve fibre immunoreactive for NPY and TH, which may have a modulatory role on the sensory receptor.