Callosal projections establish topographically organized maps between cortical areas. Neuropilin-1 (Nrp1) cortical gradient induces an early segregation of developing callosal axons. We investigated later roles of Nrp1 on the development of callosal projections from layer (L) 2/3 of the primary (S1) and secondary (S2) somatosensory (SS) areas, which express higher and lower levels of Nrp1, respectively. We used in utero electroporation to knock down or overexpress Nrp1 combined with retrograde tracers, to map connections at postnatal day 16 and 30. High levels of Nrp1 blocked contralateral S2 innervation while promoted the late postnatal growth of homotopic S1L2/3 and heterotopic S2L2/3 branches into S1. Conversely, knocking down Nrp1 increased the growth of heterotopic S1L2/3 projections into S2, and the overall refinement of S2L2/3 branches, thereby diminishing the number of P30 S2L2/3 callosally projecting neurons. Thus, the Nrp1 gradient determines homotopic SSL2/3 callosal connectivity by regulating late postnatal branching and refinement in a topographic manner.

Axons of the corpus callosum (CC) mediate the interhemispheric communication required for complex perception in mammals. In the somatosensory (SS) cortex, the CC exchanges inputs processed by the primary (S1) and secondary (S2) areas, which receive tactile and pain stimuli. During early postnatal life, a multistep process involving axonal navigation, growth, and refinement, leads to precise CC connectivity. This process is often affected in neurodevelopmental disorders such as autism and epilepsy. We herein show that in mice, expression of the axonal signaling receptor Neuropilin 1 (Nrp1) in SS layer (L) 2/3 is temporary and follows patterns that determine CC connectivity. At postnatal day 4, Nrp1 expression is absent in the SS cortex while abundant in the motor area, creating a sharp border. During the following 3 weeks, Nrp1 is transiently upregulated in subpopulations of SS L2/3 neurons, earlier and more abundantly in S2 than in S1. In vivo knock-down and overexpression experiments demonstrate that transient expression of Nrp1 does not affect the initial development of callosal projections in S1 but is required for subsequent S2 innervation. Moreover, knocking-down Nrp1 reduces the number of S2L2/3 callosal neurons due to excessive postnatal refinement. Thus, an exquisite temporal and spatial regulation of Nrp1 expression determines SS interhemispheric maps.

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