Striking parallels between carotid body glomus cell and adrenal chromaffin cell development (original) (raw)
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Transcription Factor Networks Specify Sympathetic and Adrenal Chromaffin Cell Differentiation
The identification of mechanisms leading to the restriction of lineage potential and cell fate specification of multipotential progenitor cells falls within the purview of the developmental biologist. In specific, neural crest (NC) cell differentiation has long been a favored model process to examine how environmental cues cooperate with cell intrinsic factors to specify the birth of multiple cell lineages, including sympathetic and adrenal chromaffin (SA) cells. Over the years, a handful of genes (MASH-1, Phox2a/b, Hand2, GATA-2/3) have been identified that, when their expression patterns are perturbed, lead to a variable degree of disruption in SA cell development, function and tissue-specific gene expression profiles. These genes have historically been thought to act in a monotonous, linear fashion (e.g. gene product A regulates gene B, whose product in turn regulates gene C). Recent genetic studies in mice and other model organisms provide substantial evidence to indicate that these regulatory effectors may interact in a non-linear, self-sustaining feedback network. This review summarizes our current knowledge of the five principal players that partake in the transcriptional regulatory circuitry that is employed during SA cell development.
Gene Expression Patterns, 2011
The hallmark of Parkinson's Disease is the degenerative loss of mesencephalic dopaminergic (mDA) neurons. Previous studies have shown that the homeobox transcription factors, engrailed-1 and -2, are essential for the survival of these cells. To identify genes downstream of engrailed-1 and -2, we performed a PCR-based differential display, comparing RNA from engrailed-1/2 double mutant and wild type ventral midbrain of different embryonic ages to adult olfactory bulb, a source of unrelated DA neurons. Here, we report the result of this experiment and describe the developmental expression pattern in the ventral midbrain of three of the isolated genes, HNF3a, synaptotagmin I, and Ebf3. Though not regulated by engrailed-1 and -2, the expression of all three genes is limited to mDA neurons and a few other brain areas. HNF3a appears in the precursors of mDA neurons at E9 and is expressed in the adult brain almost exclusively by this neuronal population. Synaptotagmin I is expressed from E14 into adulthood. Ebf3, in contrast, is transiently expressed during early postmitotic differentiation.
Adrenal chromaffin cells as transplants in animal models of parkinson's disease
Journal of Electron Microscopy Technique, 1989
The field of neural transplantation has moved rapidly forward in the last decade. Initially, fetal cells were used as implants to investigate their potential to ameliorate deficits in animal models of Parkinson's disease. However, because of the moral and legal problems associated with the use of fetal tissues in humans, alternative sources of donor tissue were sought which possessed the structural and functional characteristics needed to improve motor function in Parkinsonian patients. To date, one of the most promising tissues being investigated is the adrenal medulla, whose chromaffin cells possess an inherent plasticity of form and function. Transplanted chromaffin cells currently are being studied by a variety of approaches, including electron microscopy, in mouse, rat, and primate models of Parkinson's disease. An overview of the role of the chromaffin cell in this exciting and clinically important arena is briefly reviewed, with an emphasis on the fine structure of implanted chromaffin cells.
Nature Genetics, 2020
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012
Neural crest cell specification and differentiation to a sympathetic neuronal fate serves as an important model for neurogenesis and depends upon the function of both bHLH transcription factors, notably Hand2, and homeodomain transcription factors, including Phox2b. Here, we define a 1007 bp cis-regulatory element 5' of the Hand1 gene sufficient to drive reporter expression within the sympathetic chain of transgenic mice. Comparative genomic analyses uncovered evolutionarily conserved consensus-binding sites within this element, which chromatin immunoprecipitation and electrophoretic mobility shift assays confirm are bound by Hand2 and Phox2b. Mutational analyses revealed that the conserved Phox2 and E-box binding sites are necessary for proper cis-regulatory element activity, and expression analyses on both Hand2 conditionally null and hypomorphic backgrounds demonstrate that Hand2 is required for reporter activation in a gene dosage-dependent manner. We demonstrate that Hand2...
Developmental Biology, 2008
Neural crest-derived structures that depend critically upon expression of the basic helix-loop-helix DNA binding protein Hand2 for normal development include craniofacial cartilage and bone, the outflow tract of the heart, cardiac cushion, and noradrenergic sympathetic ganglion neurons. Loss of Hand2 is embryonic lethal by E9.5, obviating a genetic analysis of its in-vivo function. We have overcome this difficulty by specific deletion of Hand2 in neural crest-derived cells by crossing our line of floxed Hand2 mice with Wnt1-Cre transgenic mice. Our analysis of Hand2 knock-out in neural crest-derived cells reveals effects on development in all neural crest-derived structures where Hand2 is expressed. In the autonomic nervous system, conditional disruption of Hand2 results in a significant and progressive loss of neurons as well as a significant loss of TH expression. Hand2 affects generation of the neural precursor pool of cells by affecting both the proliferative capacity of the progenitors as well as affecting expression of Phox2a and Gata3, DNA binding proteins important for the cell autonomous development of noradrenergic neurons. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting differentiation and cell type-specific gene expression in neural crest-derived noradrenergic sympathetic ganglion neurons. Hand2 has a pivotal function in a non-linear cross-regulatory network of DNA binding proteins that affect cell autonomous control of differentiation and cell type-specific gene expression.
Development, 2018
The adrenal medulla is composed of neuroendocrine chromaffin cells that secrete adrenaline into the systemic circulation to maintain physiological homeostasis and enable the autonomic stress response. How chromaffin cell precursors colonise the adrenal medulla, and how they become connected to central nervous system derived preganglionic sympathetic neurons remains largely unknown. By combining lineage tracing, gene expression studies, genetic ablation and the analysis of mouse mutants, we demonstrate that preganglionic axons direct chromaffin cell precursors into the adrenal primordia. We further show that preganglionic axons and chromaffin cell precursors require class 3 semaphorin (SEMA3) signalling through neuropilins (NRP) to target the adrenal medulla. Thus, SEMA3s serve as guidance cues to control formation of the adrenal neuroendocrine system by establishing appropriate connections between preganglionic neurons and adrenal chromaffin cells that regulate the autonomic stress ...
The carotid body: a physiologically relevant germinal niche in the adult peripheral nervous system
Cellular and Molecular Life Sciences, 2018
The carotid body (CB) is the principal arterial chemoreceptor that mediates the hyperventilatory response to hypoxia. Our understanding of CB function and its role in disease mechanisms has progressed considerably in the last decades, particularly in recent years. The sensory elements of the CB are the neuron-like glomus cells, which contain numerous transmitters and form synapses with afferent sensory fibers. The activation of glomus cells under hypoxia mainly depends on the modulation of O 2-sensitive K + channels which leads to cell depolarization and the opening of Ca 2+ channels. This model of sensory transduction operates in all mammalian species studied thus far, including man. However, the molecular mechanisms underlying the modulation of ion channel function by changes in the O 2 level are as yet unknown. The CB plays a fundamental role in acclimatization to sustained hypoxia. Mice with CB atrophy or patients who have undergone CB resection due to surgical treatments show a marked intolerance to even mild hypoxia. CB growth under hypoxia is supported by the existence of a resident population of neural crest-derived stem cells of glia-like phenotype. These stem cells are not highly affected by exposure to low O 2 tension; however, there are abundant synapse-like contacts between the glomus cells and stem cells (chemoproliferative synapses), which may be needed to trigger progenitor cell proliferation and differentiation under hypoxia. CB hypo-or hyperactivation may also contribute to the pathogenesis of several prevalent human diseases.
The EMBO journal, 2016
Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, open...