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How developing brains mechanically interact with the surrounding embryonic scalp layers (ie, epidermal and mesenchymal) in the preosteogenic head remains unknown. Between embryonic day (E) 11 and E13 in mice, before ossification starts in the skull vault, the angle between the pons and the medulla decreases, raising the possibility that when the elastic scalp is directly pushed outward by the growing brain and thus stretched, it recoils inward in response, thereby confining and folding the brain.Stress-release tests showed that the E11-13 scalp recoiled and that the in vivo prestretch prerequisite for this recoil was physically dependent on the brain (pressurization at 77-93 Pa) and on actomyosin and elastin within the scalp. In scalp-removed heads, brainstem folding was reduced, and the spreading of ink from the lateral ventricle to the spinal cord that occurred in scalp-intact embryos (with5 μL injection) was lost, suggesting roles of the embryonic scalp in brain morphogenesis and cerebrospinal fluid homeostasis. Under nonstretched conditions, scalp cell proliferation declined, while the restretching of the shrunken scalp rescued scalp cell proliferation.In the embryonic mouse head before ossification, a stretcher-compressor relationship elastically develops between the brain and the scalp, underlying their mechanically interdependent development.

During brain enlargement between embryonic day (E) 11 and E13, within the limited mouse cranial space enclosed by the scalp consisting of epidermal and preosteogenic mesenchymal layers, the angle between the pons and the medulla decreases. This raises the possibility that the scalp, upon being pushed outwardly by the brain and stretched, in return inwardly recoils to confine and fold the brain. Our stress-releasing tests showed that the scalp recoiled to shrink more extensively at E12~13 than at E15~16 and that the in vivo pre-stretch prerequisite for this recoil response depended physically on the brain (pressurization at 77~93 Pa) and on actomyosin and elastin within the scalp layers. Under non-stretched conditions, scalp cell proliferation declined, while re-stretching of the shrunken scalp rescued proliferation. In scalp-removed heads, pons–medulla folding was reduced, and the spreading of ink from the lateral ventricle to the spinal cord that occurred in scalp-intact embryos (with >5 μl injection) was lost, suggesting that the scalp plays roles in brain morphogenesis and cerebrospinal fluid homeostasis. Thus, the brain and the scalp mechanically interact and collaborate.