Establishing brain functional laterality in adult mice through unilateral gene manipulation in the embryonic cortex

Brain functional laterality appears either in individuals or in a population in vertebrates, though the degree of asymmetry varies^1,2. Behavioral asymmetry such as paw preference, a food reaching skill, is observed in individual mice to a certain degree in some strains, but not on a larger population level and not in all strains³. The hemisphere with the larger motor cortex tends to be dominant in controlling manual skills, leading to a stronger preference of using the contralateral front paw^4,5. However, the mechanism underlying the establishment of the dominant functional areas in the left or right hemispheres is poorly understood^6,7.

We next tested whether unilateral knockdown of Lmo4 alters the organization of cortical functional areas by examining the expression pattern of several cortical regional markers. Compared with the left hemisphere with no electroporation, Cdh8 anterior expression was greatly reduced, and the anterior expression of Auts2 and Ror β shifted rostrally in the right hemisphere of Lmo4^f/f;A-iCre mice (Supplementary information, Figure S1). The numbers of both early-born (Tbr1⁺ and Ctip2⁺) and late-born neurons (Cux1⁺) were greatly reduced in the coronal sections of E17.5 and P0 right hemispheres that received iCre (visible by GFP staining) electroporation at E14.5, compared with those in the left hemisphere sections (Figure 1H-1L and Supplementary information, Figures S2-S4). However, perturbed neurogenesis was recovered in adult brains (Supplementary information, Figure S5). Furthermore, axonal projections from the right hemisphere were significantly thinner than those from the left, as determined by neural cell adhesion molecule L1 labeling and by DiI tracing in P0 and P16 Lmo4^f/f;A-iCre mice, respectively (Supplementary information, Figure S6). Consistent with the role of Lmo4 in specifying neuronal subtypes in the motor cortex¹⁰, our results indicate that unilateral depletion of Lmo4 expression in embryonic cortices is sufficient to suppress early neurogenesis in one hemisphere, and results in asymmetric functional area formation, neuronal production and axonal projection.

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