Ectopic myelinating oligodendrocytes in the dorsal spinal cord as a consequence of altered semaphorin 6D signaling inhibit synapse formation

Abstract

SUMMARYDifferent types of sensory neurons in the dorsal root ganglia project axons to the spinal cord to convey peripheral information to the central nervous system. Whereas most proprioceptive axons enter the spinal cord medially, cutaneous axons typically do so laterally. Because heavily myelinated proprioceptive axons project to the ventral spinal cord, proprioceptive axons and their associated oligodendrocytes avoid the superficial dorsal horn. However, it remains unclear whether their exclusion from the superficial dorsal horn is an important aspect of neural circuitry. Here we show that a mouse null mutation of Sema6d results in ectopic placement of the shafts of proprioceptive axons and their associated oligodendrocytes in the superficial dorsal horn, disrupting its synaptic organization. Anatomical and electrophysiological analyses show that proper axon positioning does not seem to be required for sensory afferent connectivity with motor neurons. Furthermore, ablation of oligodendrocytes from Sema6d mutants reveals that ectopic oligodendrocytes, but not proprioceptive axons, inhibit synapse formation in Sema6d mutants. Our findings provide new insights into the relationship between oligodendrocytes and synapse formation in vivo, which might be an important element in controlling the development of neural wiring in the central nervous system.

Axon Guidance in the Spinal Cord

“…Genetic deletion of oligodendrocytes demonstrates that it is the ectopic oligodendrocytes, not the proprioceptive axons, in the dorsal spinal cord that inhibit synapse formation in the absence of Sema6D-plexin-A1 signaling (Fig. 3.3a, right) (Leslie et al 2011). These studies provide new insights into the roles of oligodendrocytes in synapse formation in vivo, which may be an important element regulating the overall development of neural wiring in the central nervous system (CNS).…”

“…Two studies demonstrate the role of the plexin-A1 receptor and its ligand Sema6D in proprioceptive sensory axon positioning in the dorsal spinal cord and their effects on cutaneous sensory axons (Yoshida et al 2006;Leslie et al 2011). Plexin-A1 is exclusively expressed by proprioceptive sensory neurons in the DRG, whereas Sema6D is expressed in the dorsal spinal cord (Fig.…”

“…In plexin-A1 or Sema6D mutants, proprioceptive axons ectopically invade the dorsal horn (Fig. 3.3a, middle) (Yoshida et al 2006;Leslie et al 2011). Proprioceptive axons are heavily myelinated whereas most cutaneous axons either have no myelination or are only thinly myelinated (Fig.…”

“…Although the oligodendrocytes associated with the ectopic proprioceptive axons in plexin-A1 or Sema6D mutants synchronously invade the dorsal spinal cord (Fig. 3.3a, middle) (Yoshida et al 2006;Leslie et al 2011), the axonal trajectories of cutaneous sensory neurons are unaffected. However, these cutaneous sensory neurons are unable to form appropriate synapses with dorsal spinal cord neurons (Fig.…”

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

“…Multiple receptors and coreceptors are engaged by semaphorins, mediating downstream signaling that regulates neuronal migration (Chen et al 2008a), synapse formation (Leslie et al 2011), and synaptic transmission (Sahay et al 2005). Semaphorins are also key regulators of angiogenesis, the immune system, cancer progression and tumorigenesis, and cytoskeletal organization in a wide range of cell types (Kruger et al 2005;Yazdani and Terman 2006).…”