Crim1 and Kelch-like 14 exert complementary dual-directional developmental control over segmentally specific corticospinal axon projection targeting.

The cerebral cortex executes highly skilled movement, necessitating that it connects accurately with specific brainstem and spinal motor circuitry. Corticospinal neurons (CSN) must correctly target specific spinal segments, but the basis for this targeting remains unknown. In the accompanying report, we show that segmentally distinct CSN subpopulations are molecularly distinct from early development, identifying candidate molecular controls over segmentally specific axon targeting. Here, we functionally investigate two of these candidate molecular controls, Crim1 and Kelch-like 14 (Klhl14), identifying their critical roles in directing CSN axons to appropriate spinal segmental levels in the white matter prior to axon collateralization. Crim1 and Klhl14 are specifically expressed by distinct CSN subpopulations and regulate their differental white matter projection targeting-Crim1 directs thoracolumbar axon extension, while Klhl14 limits axon extension to bulbar-cervical segments. These molecular regulators of descending spinal projections constitute the first stages of a dual-directional set of complementary controls over CSN diversity for segmentally and functionally distinct circuitry.