Scientific Understanding of Consciousness
Astrocyte Local Position Cues Sensorimotor
Nature 509, 189–194 (08 May 2014)
Astrocyte-encoded positional cues maintain sensorimotor circuit integrity
Anna V. Molofsky, et.al.
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA
Department of Psychiatry, University of California San Francisco, San Francisco, California 94143, USA
Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA
Medical Scientist Training Program, University of California San Francisco, San Francisco, California 94143, USA
Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94143, USA
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA
Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA
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.
Developing neural circuits must form and maintain appropriate regional connections in a rapidly expanding central nervous system (CNS). Although astrocytes (AS) are increasingly recognized as general regulators of synapse formation, little is known about whether they encode heterogeneous positional signals involved in local neural circuit formation and/or maintenance. Recent studies indicate that AS develop and are regionally allocated in murine brain and spinal cord (SC) according to an embryonic segmental template. AS derived from embryonic radial glia migrate in the trajectory of these fibres and proliferate locally, yielding clonally related populations that retain spatial restriction into adulthood.
Here we tested whether AS allocated to discrete dorsal–ventral (DV) SC domains might be functionally adapted to support specific neural circuits and neuronal subtypes. The SC sensorimotor circuit has well-defined organization in the DV axis. The ventral horn contains two types of motor neurons (MN), called α-MN and γ-MN, whose axons exit the ventral root to project to extrafusal (α) and intrafusal (γ) muscle fibres. During development, afferent sensory fibres entering from the dorsal root ganglion (DRG) include type 1a proprioceptive afferents that synapse directly on ventral α-MN, and TrkA+ sensory axons that synapse in the dorsal grey matter.
Although programs that control MN diversification and connectivity are well established, comparatively little is known about non-neuronal signals that influence local circuit formation. We report that ventral AS-encoded semaphorin 3a (Sema3a), a secreted molecule that signals through plexin A/neuropilin 1 receptor (Nrp1) complexes, has critical roles in orienting MN axon initial segments (AIS), synapse regulation, MN subtype survival and normal patterning of a subset of TrkA+ sensory neurons. These findings establish a discrete molecular function for region-restricted AS.
We propose that region-restricted AS comprise a stable ‘scaffold’ that maintains positional information throughout embryonic and postnatal development. This positional code is necessary for proper circuit formation, refinement and neuronal survival in a subtype-specific manner. Loss of Sema3a function from AS led to a sequence of α-MN-specific phenotypes, comprising defective postnatal maintenance of AIS orientation, markedly abnormal inhibitory and excitatory currents in MN and abnormal synapse investment, and finally, α-MN loss. Concomitantly, in more dorsal regions, AS-encoded Sema3a acts to repel TrkA sensory afferent fibres in a subtype-specific manner. It is possible that these phenotypes represent a pathological progression, or alternatively, that ventral AS-encoded Sema3a has multiple coordinated functions that determine structural and functional sensorimotor circuit integrity.
Our in vitro studies further suggest that AS positional identity is at least partly cell intrinsic, as cognate Sema3a-dependent regional AS properties were retained in co-cultures independent of local environmental cues. As such, a testable prediction is that embryonic CNS patterning mechanisms might establish a template for generation of heterogeneous properties of AS. Furthermore, although maintenance of MN axonal orientation represents one tropic effect of AS-encoded Sema3a, further investigation is needed to assess other potential roles of this or other AS-encoded regional cues, such as promoting dendrite growth, maintenance of neuronal soma position, local synaptic strength and/or sensorimotor specificity.
Specialized local functions of AS in neural circuit formation may also have significance in human disease. For example, loss of ventral SC MN in amyotrophic lateral sclerosis (ALS) has been associated with mutant superoxide dismutase protein in ventral AS in animal models of the disease. Our findings suggest the possibility that the unique identity of ventral horn AS might lead to deficient local support for MN and disease progression in ALS. More generally, given that AS are regionally patterned throughout the CNS, the concept of regional AS function and dysfunction has implications for a variety of neurodevelopmental and psychiatric disorders.
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