Role of Nrp1 in controlling cortical inter-hemispheric circuits

Abstract

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.

Early cortical GABAergic interneurons determine the projection patterns of L4 excitatory neurons

“…Next, we studied changes across different postnatal stages resulting from P2 to P5 diazepam treatment. In a canonical scenario, S1L4 transient interhemispheric axons grow during P1 to P7 and undergo a steady elimination from P10 to P21 ( 8 , 21 ). In electroporated animals, analyzed at P6, IUE + callosal axons from L4 showed similar trajectories, lengths, and midline occupancy in control and treated animals (fig.…”

“…For the analysis of the IUE, measures of the ipsilateral somas and the contralateral innervation were performed as previously reported ( 8 ). To check for comparable IUE efficiency, we quantified the total number and distribution of electroporated neurons in a semiautomated manner using an ImageJ custom macro already used in (https://doi.org/10.5281/zenodo.10423646) ( 21 ). Briefly, the entire electroporated region was outlined, and cortical layers were separated on the basis of their distinct cell densities.…”

Molecular mechanisms of corpus callosum development: a four-step journey

“…Interaction between Sema3C and its receptor Nrp1 initiates the process of attraction of pioneer axons toward the midline. However, after midline crossing, the Nrp1/Sema3C signaling is suppressed by EphrinB1 ( Mire et al, 2018 ; Martín-Fernández et al, 2022 ). Pre-crossing CC axons express Nrp1 and are responsive to Sema3C, contrary to EphrinB1 whose expression is absent in these axons.…”

Nrg1 intracellular signaling regulates the development of interhemispheric callosal axons in mice

“…Notably, the development of CC is a complex process that begins during embryonic development, when callosal projecting neurons extend their axons medially, and continues into late postnatal stages of cortical development with the precise targeting of their contralateral counterparts ( de León Reyes et al, 2020 ). Different guidance cues regulate the wiring of CC fibers, and the precise timing of CC development is critical for the proper formation of cortical circuits ( Piper et al, 2009 ; Martín-Fernández et al, 2022 ).…”