TY - JOUR
T1 - Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension
AU - Iyer, Manasi
AU - Kantarci, Husniye
AU - Cooper, Madeline H.
AU - Ambiel, Nicholas
AU - Novak, Sammy Weiser
AU - Andrade, Leonardo R.
AU - Lam, Mable
AU - Jones, Graham
AU - Münch, Alexandra E.
AU - Yu, Xinzhu
AU - Khakh, Baljit S.
AU - Manor, Uri
AU - Zuchero, J. Bradley
N1 - We thank current and past members of the Zuchero lab (especially the OPC Crew: Maya Weigel and Miguel Garcia), Michael Burks, and Ganesh and Neeraja Iyer for their helpful discussions and support. We thank and remember Kevin Forsythe for his technical assistance in the early stage of the project and thank Ethan Hughes for providing insightful feedback on the manuscript. We thank Klaus Nave for kindly sharing the Cnp-Cre mouse line. We also thank the Stanford University Cell Sciences Imaging Core Facility for Transmission Electron Microscopy data collection, especially John Perrino and Ibanri Phanwar-Wood for their expertise in processing and staining EM samples (RRID:SCR_017787: supported by an ARRA Award Number 1S10RR026780-01 from the National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health.). Electron microscopy image processing was supported in part by the grants: NN1 NSF 1707356 and NN2 NSF 2014862. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC and visualization resources that have contributed to the research results reported within this paper. We also thank the Stanford Neuroscience Gene Vector and Virus Core for producing the adeno-associated viruses used in this study. Images and diagrams were created using BioRender.com. This project was supported by the Regina Casper Stanford Graduate Fellowship (M.I.), Stanford Berry Postdoctoral Fellowship (H.K.), Stanford Medical Scientist Training Program [T32 GM007365-45] and Stanford Bio-X Interdisciplinary Graduate Fellowship (M.H.C.), Waitt Foundation and Core Grant application NCI CCSG (CA014195) (S.W.N, L.R.A, U.M.), Helen Hay Whitney Foundation (M.L.), Stanford Wu Tsai Neurosciences Interdisciplinary Scholar Award (M.L.), NINDS R35NS111583 (X.Y. and B.S.K.), Chan-Zuckerberg Imaging Scientist Grant (U.M), NSF Neuronex Grant 2014862 (U.M.), the McKnight Endowment Fund for Neuroscience (J.B.Z.), the Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program (IIP) [R9-24] (J.B.Z.), the National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar Award (J.B.Z.), the Beckman Young Investigator Award (J.B.Z.), the Myra Reinhard Family Foundation (J.B.Z.), the National Institutes of Health R01NS119823 (J.B.Z.), and the Koret Family Foundation (J.B.Z.).
We thank current and past members of the Zuchero lab (especially the OPC Crew: Maya Weigel and Miguel Garcia), Michael Burks, and Ganesh and Neeraja Iyer for their helpful discussions and support. We thank and remember Kevin Forsythe for his technical assistance in the early stage of the project and thank Ethan Hughes for providing insightful feedback on the manuscript. We thank Klaus Nave for kindly sharing the Cnp-Cre mouse line. We also thank the Stanford University Cell Sciences Imaging Core Facility for Transmission Electron Microscopy data collection, especially John Perrino and Ibanri Phanwar-Wood for their expertise in processing and staining EM samples (RRID:SCR_017787: supported by an ARRA Award Number 1S10RR026780-01 from the National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health.). Electron microscopy image processing was supported in part by the grants: NN1 NSF 1707356 and NN2 NSF 2014862. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC and visualization resources that have contributed to the research results reported within this paper. We also thank the Stanford Neuroscience Gene Vector and Virus Core for producing the adeno-associated viruses used in this study. Images and diagrams were created using BioRender.com. This project was supported by the Regina Casper Stanford Graduate Fellowship (M.I.), Stanford Berry Postdoctoral Fellowship (H.K.), Stanford Medical Scientist Training Program [T32 GM007365-45] and Stanford Bio-X Interdisciplinary Graduate Fellowship (M.H.C.), Waitt Foundation and Core Grant application NCI CCSG (CA014195) (S.W.N, L.R.A, U.M.), Helen Hay Whitney Foundation (M.L.), Stanford Wu Tsai Neurosciences Interdisciplinary Scholar Award (M.L.), NINDS R35NS111583 (X.Y. and B.S.K.), Chan-Zuckerberg Imaging Scientist Grant (U.M), NSF Neuronex Grant 2014862 (U.M.), the McKnight Endowment Fund for Neuroscience (J.B.Z.), the Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program (IIP) [R9-24] (J.B.Z.), the National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar Award (J.B.Z.), the Beckman Young Investigator Award (J.B.Z.), the Myra Reinhard Family Foundation (J.B.Z.), the National Institutes of Health R01NS119823 (J.B.Z.), and the Koret Family Foundation (J.B.Z.).
PY - 2024/12
Y1 - 2024/12
N2 - Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length are thought to precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation remains incompletely understood. Here, we use genetic tools to attenuate oligodendrocyte calcium signaling during myelination in the developing mouse CNS. Surprisingly, genetic calcium attenuation does not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation causes myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduces actin filaments in oligodendrocytes, and an intact actin cytoskeleton is necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a cellular mechanism required for accurate CNS myelin formation and may provide mechanistic insight into how oligodendrocytes respond to neuronal activity to sculpt and refine myelin sheaths.
AB - Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length are thought to precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation remains incompletely understood. Here, we use genetic tools to attenuate oligodendrocyte calcium signaling during myelination in the developing mouse CNS. Surprisingly, genetic calcium attenuation does not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation causes myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduces actin filaments in oligodendrocytes, and an intact actin cytoskeleton is necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a cellular mechanism required for accurate CNS myelin formation and may provide mechanistic insight into how oligodendrocytes respond to neuronal activity to sculpt and refine myelin sheaths.
UR - https://www.scopus.com/pages/publications/85181479244
UR - https://www.scopus.com/pages/publications/85181479244#tab=citedBy
U2 - 10.1038/s41467-023-44238-3
DO - 10.1038/s41467-023-44238-3
M3 - Article
C2 - 38177161
AN - SCOPUS:85181479244
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 265
ER -