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Developmental Biology - Neurons
How Blood Vessels Talk to Neurons
Blood vessels communicate with sensory neurons to decide whether those cells remain stem cells or differentiate into neurons...
Researchers at Pompeu Fabra University show for the first time that blood vessels communicate with sensory neurons located in the peripheral nervous system. This is how neurons are regulated and proliferate.
The study is published in the journal Cell Reports and was conducted using zebrafish as a model. It was led by Berta Alsina PhD, principal investigator of the Morphogenesis and Cell Signaling in Sensory Systems group, with the assistance of Laura Taberner and Aitor Bañón.
Researchers, using real-time videos, obervered that both neurons and blood vessel cells emit dynamic protrusions able to 'talk' to each other. Called signalling filopodia or cytonemes these protrusions have a receptor or ligand at their tip allowing them to send signals. Only very recently discovered, it's a highly precise signalling mechanism, both in space and in time.
"It was known blood vessel cells and stem cells in the brain communicate. But, this is the first time it was witnessed via cytonemes in the peripheral nervous system. Using high resolution spatio-temporal visualization techniques in vivo, we saw it happen in real time. Cytonemes might also exist in the brain."
Berta Alsina PhD, Developmental Biology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra—Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
This system of communication allows some precursors of neurons to remaiin in a quiescence state — dormant, constituting a reservoir of stem cells. Thus, if later on in adulthood an injury occurs, quiescent cells can be activated to replace damaged neurons.
"If all neuronal precursor cells proliferate and differentiate, we wouldn't have this reservoir — and there wouldn't be any opportunity for regeneration in the auditory and vestibular system. This is why we are studying cases of deafness as, latter, vertigo may arise."
Laura Taberner PhD, , Developmental Biology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra—Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain, and first author of the study.
The study also concludes that the precursors are initially in a hypoxic environment, i.e., lacking oxygen, which keeps them proliferating. When blood vessels connect to each other during development, oxygen is transported by the blood vessels and the environment becomes normoxic. The researchers have found that oxygen is the second signal of the vessels and in this case, instead of regulating quiescence, oxygen regulates the differentiation of neuronal precursors to neurons.
The study shows that during development of the peripheral nervous system, formation of new neurons and maintenance of stem cells depends on signals from blood vessels.
Neurons receive signals from all surrounding cells, as part of the environment in which they reside. Blood vessels are part of this niche.
"This new knowledge will help us understand the connection between hearing loss and cardiovascular diseases, as well as improve protocols for in vitro differentiation of neurons for regenerative therapies."
Laura Taberner PhD.
Abstract
Highlights
• Vasculature is part of the cranial sensory ganglia niche and regulates neurogenesis
• Neurovascular cytoneme contacts are required for neuroblast quiescence
• Dll4-Notch signaling regulates the growth of cranial sensory ganglia
• Blood flow triggers a transcriptional metabolic switch and neuronal differentiation.
Summary
In many organs, stem cell function depends on communication with their niche partners. Cranial sensory neurons develop in close proximity to blood vessels; however, whether vasculature is an integral component of their niches is yet unknown. Here, two separate roles for vasculature in cranial sensory neurogenesis in zebrafish are uncovered. The first involves precise spatiotemporal endothelial-neuroblast cytoneme contacts and Dll4-Notch signaling to restrain neuroblast proliferation. The second, instead, requires blood flow to trigger a transcriptional response that modifies neuroblast metabolic status and induces sensory neuron differentiation. In contrast, no role of sensory neurogenesis in vascular development is found, suggesting unidirectional signaling from vasculature to sensory neuroblasts. Altogether, we demonstrate that the cranial vasculature constitutes a niche component of the sensory ganglia that regulates the pace of their growth and differentiation dynamics.
Authors
Laura Taberner, Aitor Bañón and Berta Alsina.
Acknowledgements
The authors thank D. Stainer for the Tg(cloche) m378 and Tg(kdrl:ras-mCherry) s896 lines; M. Affolter for the Tg(fli1ep:GAL4FF ubs3; UAS:RFP rk8) line; C. Pujades for the Tg(tp1:d2-GFP) mw43 line; J. Gross for the 10xuas:EGFP-f2a-Rac1a DN construct; the Parc de Recerca Biomèdica de Barcelona (PRBB) Imaging Facility and the Universitat Pompeu Fabra (UPF) Genomics Core and Flow Cytometry Facilities for technical support; T. Schilling, A. Bigas, and I. Fariñas for comments on the manuscript; and lab members for discussions. The work was supported by MINECO - BFU2014-53203-P and AEI - BFU2017-82723-P (FEDER) from Ministerio de Ciencia e Innovacion of Spain to B.A. and by the Unidad de Excelencia Maria de Maeztu (MDM-2014-0370) from Ministerio de Ciencia e Innovacion of Spain.
The authors declare no competing interests.
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Jul 20 2020 Fetal Timeline Maternal Timeline News
 Depending on the context, blood vessels regulate stem cell quiescence, proliferation, and/or differentiation. CREDIT The authors.
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