Cerebellar folding is initiated by mechanical constraints on a fluid-like layer without a cellular pre-pattern.

Andrew K Lawton,Teng Zhang,Masaaki Omura,J M Schwarz,Jonathan Mamou,Daniel H Turnbull,Tyler Engstrom,Alexandra L Joyner,Daniel Rohrbach

doi:10.7554/elife.45019

Abstract

Models based in differential expansion of elastic material, axonal constraints, directed growth, or multi-phasic combinations have been proposed to explain brain folding. However, the cellular and physical processes present during folding have not been defined. We used the murine cerebellum to challenge folding models with in vivo data. We show that at folding initiation differential expansion is created by the outer layer of proliferating progenitors expanding faster than the core. However, the stiffness differential, compressive forces, and emergent thickness variations required by elastic material models are not present. We find that folding occurs without an obvious cellular pre-pattern, that the outer layer expansion is uniform and fluid-like, and that the cerebellum is under radial and circumferential constraints. Lastly, we find that a multi-phase model incorporating differential expansion of a fluid outer layer and radial and circumferential constraints approximates the in vivo shape evolution observed during initiation of cerebellar folding.

Highlights

Models based in differential expansion of elastic material, axonal constraints, directed growth, or multi-phasic combinations have all been proposed to explain brain folding
We demonstrate that the expansion of the external granule cell layer (EGL) is uniform, and fluid-like, and that the cerebellum is under radial and circumferential constraints when folding initiates
Since the cerebellum is under circumferential tension, as demonstrated above, we examined evidence of radial tension between the EGL and the ventricular zone (VZ) at the initiation of folding

Summary

Introduction

Models based in differential expansion of elastic material, axonal constraints, directed growth, or multi-phasic combinations have all been proposed to explain brain folding. To test whether the cerebellum has differential expansion between the two layers, we measured the expansion of the EGL and the core during the time of initiation of folding from midline sagittal sections (Fig 1a-d).

Results

Conclusion