Article | Published:

Astrocyte-encoded positional cues maintain sensorimotor circuit integrity

Nature volume 509, pages 189194 (08 May 2014) | Download Citation

Abstract

Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help to refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded semaphorin 3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated α-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α- but not of adjacent γ-motor neurons. In addition, a subset of TrkA+ sensory afferents projects to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement.

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Gene Expression Omnibus

Data deposits

Microarray data has been deposited to GEO under accession number GSE55054.

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Acknowledgements

We thank J. Flanagan, T. Jessell, J. de Nooj, N. Balaskas, M. Hancock, S. Ohata and R. Krencik for comments on the manuscript and technical suggestions. We are grateful to K. Sabeur, M. Wong and the UCSF Flow Cytometry and Genomics core facilities for expert technical help, A. Kolodkin for Sema3a probe construct, L. Reichardt for the TrkA antibody, J. Dasen for FoxP1 and Scip antibodies, and N. Heintz and J. Dougherty for Aldh1L1-cre mice. A.V.M. is supported by an NIMH Training Grant (5T32MH089920-04) and an APA/Pfizer MD/PhD Psychiatric Research Fellowship. K.W.K is supported by the California Institute for Regenerative Medicine (TG2-01153). S.A.R. is supported by a Ruth L. Kirschstein NRSA FNS081905A. This work was supported by grants from the NINDS (to D.H.R. (R01 NS059893) and J.R.C.), E.M.U. is supported by NIMH (R01MH099595-01), an NIH New Innovator Award (1DP2OD006507-01) and That Man May See. D.H.R. is a HHMI Investigator.

Author information

Author notes

    • Kevin W. Kelley
    •  & Hui-Hsin Tsai

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA

    • Anna V. Molofsky
    • , Kevin W. Kelley
    • , Hui-Hsin Tsai
    • , Sandra M. Chang
    •  & David H. Rowitch
  2. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA

    • Anna V. Molofsky
    • , Kevin W. Kelley
    • , Hui-Hsin Tsai
    • , Sandra M. Chang
    •  & David H. Rowitch
  3. Department of Psychiatry, University of California San Francisco, San Francisco, California 94143, USA

    • Anna V. Molofsky
  4. Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA

    • Kevin W. Kelley
    • , Hui-Hsin Tsai
    •  & David H. Rowitch
  5. Medical Scientist Training Program, University of California San Francisco, San Francisco, California 94143, USA

    • Kevin W. Kelley
  6. Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94143, USA

    • Kevin W. Kelley
    •  & Stephanie A. Redmond
  7. Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA

    • Stephanie A. Redmond
    • , Lohith Madireddy
    • , Jonah R. Chan
    •  & Sergio E. Baranzini
  8. Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA

    • Erik M. Ullian
  9. Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA

    • David H. Rowitch

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Contributions

A.V.M. performed most experiments and data analysis. K.W.K performed electrophysiology under supervision of E.M.U. H.-H.T. contributed to data analysis and experimental design. S.A.R. performed MN purification under supervision of J.R.C. S.M.C performed mouse genotyping. L.M. and S.E.B. performed bioinformatics data processing and analysis. A.V.M. and D.H.R. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David H. Rowitch.

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DOI

https://doi.org/10.1038/nature13161

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