Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.
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.
1] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA [3] Department of Psychiatry, University of California San Francisco, San Francisco, California 94143, USA.
Anna V
AV
Molofsky
1] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA [3] Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA [4] Medical Scientist Training Program, University of California San Francisco, San Francisco, California 94143, USA [5] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94143, USA [6].
Kevin W
KW
Kelley
1] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA [3] Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA [4].
Hui-Hsin
HH
Tsai
1] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94143, USA [2] Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
Stephanie A
SA
Redmond
1] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
Sandra M
SM
Chang
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
Lohith
L
Madireddy
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
Jonah R
JR
Chan
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
Sergio E
SE
Baranzini
Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA.
Erik M
EM
Ullian
1] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA [3] Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA [4] Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA.
David H
DH
Rowitch
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D001369:Axons / Q000502:physiology; D016764:Cell Polarity; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology*; D040121:Semaphorin-3A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D013569:Synapses / Q000378:metabolism
C108639:SEMA3A protein, human; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A