Netrin1 and reelin signaling are required for the migration of anterolateral system neurons in the embryonic spinal cord

Projection neurons of the spinal cord dorsal horn which transmit pain, itch, and temperature information to the brain comprise the anterolateral system (AS). A recent molecular and genetic study showed that many developing AS neurons express the transcription factor Phox2a and provided insights into the mechanisms of their ontogeny and wiring of nociceptive neuronal circuits. Here, we show that the loss of the axonal guidance and neuronal migration signal netrinl results in impaired migration of mouse Phox2a+ AS neurons into the spinal lamina I. Furthermore, we show that in the absence of Dab1, an intracellular transducer of the neuronal migration signal reelin, the migration of spinal lamina V and lateral spinal nucleus Phox2a+ AS neurons is impaired, in line with deficits in nociception seen in mice with a loss of reelin signaling. Together, these results provide evidence that netrinl and reelin control the development of spinal nociceptive projection neurons, suggesting a mechanistic explanation for studies that link sequence variations in human genes encoding these neurodevelopmental signals and abnormal pain sensation.

Automated summary

Projection neurons in the spinal cord dorsal horn transmit pain, itch, and temperature information to the brain through the anterolateral system. Recent research has shown that Phox2a, a transcription factor, is expressed in many developing neurons in this system and has provided insights into their development and wiring of nociceptive circuits. This study reveals that the loss of the axonal guidance and neuronal migration signal netrinl leads to impaired migration of Phox2a+ neurons in the spinal lamina I. Additionally, the absence of Dab1, an intracellular transducer of the neuronal migration signal reelin, impairs the migration of Phox2a+ neurons in the spinal lamina V and lateral spinal nucleus, consistent with deficits in nociception observed in mice with a loss of reelin signaling. Collectively, these findings provide evidence that netrinl and reelin control the development of spinal nociceptive projection neurons and offer a mechanistic explanation for studies linking sequence variations in human genes encoding these neurodevelopmental signals and abnormal pain sensation.