Small Brains, Small Skulls: Effect of Cortex Specific Overexpression of BAF170 on the Mouse Cranium.

Cephalization is an important evolutionary and developmental process. Integration of the brain and skull throughout development and evolution produces brains that fit tightly within skulls. We sought to explore brain/skull integration using a mouse model that produces a small brain. Mammalian BAF170 is an intrinsic factor controlling cortical size, and cortex specific overexpression of BAF170 (conditional overexpression) which results in a mouse model in which cortical growth is inhibited. We looked at BAF170cOE mice and their unaffected littermates (controls) at various ages during cortical development, including embryonically at E15.5, as well as early post-natal timepoints (P0, P14) as the cortex grows dramatically, and timepoints approaching complete cortical and skull growth (P28, P42). Using histological sections, we determined that the area of the cortex and number of nuclei within the cortex were reduced in BAF170cOE mice as compared to unaffected littermates, particularly at post-natal time points. Using Euclidian Distance Matrix Analysis, we found no difference in skull form embryonically. Mediolateral dimensions of skulls of BAF170cOE mice were reduced by 3-10% at P0 as compared to controls. At the later post-natal time-points (P14, P28, P42) there were significant differences in skull form between genotypes. Skulls of BAF170cOE mice were reduced by almost 20% along the anteroposterior and mediolateral axes. Our data show that the BAF170cOE mouse has a cortex that is reduced in size due to fewer nuclei resulting from overexpression of BAF170. The skull is not a direct target of the BAF170 gene, yet it responds to the change in brain size and shape by adjusting its size and contours to match the brain. The mechanisms that enable that coordination, a target for our future investigation, hold the key to understanding the evolution of human skull shape and encephalization. Additionally, these investigations may identify possible targets for treatment or prevention of craniofacial birth defects.