Abstract
ABSTRACTThe 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 remain 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, SEMA3 proteins 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 response.
Highlights
Neuroendocrine chromaffin cells of the adrenal medulla produce adrenaline and noradrenaline to regulate the function of internal organs for physiological homeostasis and to initiate the ‘fight-or-flight’ stress response (Lumb and Schwarz, 2015)
Summary statement: This research demonstrates a new role for Semaphorin / Neuropilin signalling in guiding preganglionic sympathetic axons and chromaffin cell precursors into the adrenal primordia
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
Summary
Neuroendocrine chromaffin cells of the adrenal medulla produce adrenaline and noradrenaline to regulate the function of internal organs for physiological homeostasis and to initiate the ‘fight-or-flight’ stress response (Lumb and Schwarz, 2015). Paramount to correct chromaffin cell function is cholinergic input from preganglionic neurons whose cell bodies are located within the central nervous system and which project axons to the adrenal medulla to form synapses with chromaffin cells. It remains unknown how connections between preganglionic neurons and chromaffin cells are established. BMPs secreted from the dorsal aorta have been proposed to induce expression of Neuregulin 1 (NRG1) and Stromal cell-derived factor 1 (SDF1) within the para-aortic mesenchyme to act directly on the chromaffin cell precursors to promote their migration towards the adrenal primordia (Saito et al, 2012). A proportion of chromaffin cells has been suggested to arise from sympathoadrenal NCCs that first transition through an intermediate Schwann cell precursor (SCP) state: these SCPs are proposed to migrate along preganglionic sympathetic nerve fibres into the adrenal medulla, where they differentiate into chromaffin cells (Furlan et al, 2017)
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