A 2020 view of tension-based cortical morphogenesis

Abstract

Mechanical tension along the length of axons, dendrites, and glial processes has been proposed as a major contributor to morphogenesis throughout the nervous system [D. C. Van Essen, Nature 385, 313-318 (1997)]. Tension-based morphogenesis (TBM) is a conceptually simple and general hypothesis based on physical forces that help shape all living things. Moreover, if each axon and dendrite strive to shorten while preserving connectivity, aggregate wiring length would remain low. TBM can explain key aspects of how the cerebral and cerebellar cortices remain thin, expand in surface area, and acquire their distinctive folds. This article reviews progress since 1997 relevant to TBM and other candidate morphogenetic mechanisms. At a cellular level, studies of diverse cell types in vitro and in vivo demonstrate that tension plays a major role in many developmental events. At a tissue level, I propose a differential expansion sandwich plus (DES+) revision to the original TBM model for cerebral cortical expansion and folding. It invokes tangential tension and "sulcal zipping" forces along the outer cortical margin as well as tension in the white matter core, together competing against radially biased tension in the cortical gray matter. Evidence for and against the DES+ model is discussed, and experiments are proposed to address key tenets of the DES+ model. For cerebellar cortex, a cerebellar multilayer sandwich (CMS) model is proposed that can account for many distinctive features, including its unique, accordion-like folding in the adult, and experiments are proposed to address its specific tenets.

Keywords: biomechanics; cerebellum; cerebral cortex; folding; gyrification.

Fig. 1.

(A) Spherical growth bubble and isotropic expansion (green arrows) in a cubical tissue “voxel” with isotropic compliance. (B) Oblate spheroidal growth bubble in a voxel with radially biased tension (red arrows) and hence anisotropic compliance and expansion.

Fig. 2.

Key events and cellular components in a prototypical developing neuron during axonal/neurite outgrowth and cell migration. These events may occur concurrently or in any sequence.

Fig. 3.

Primate forebrain development. (A) Schematic of human coronal section at GW9. Copyright (2006) from ref. . Reproduced by permission of Taylor and Francis Group, LLC, a division of Informa plc. (B and C) Nissl-stained sections from macaque cortical area V1 at embryonic days E65 and E78, respectively, with schematics of glial and neuronal morphologies. Reprinted from ref. , by permission of Oxford University Press.

Fig. 4.

(A and B) Timing of major events in macaque (A) and human (B) cortical development. (C) Location of future insular cortex relative to claustrum (Cl), basal ganglia (BG), thalamus (Th), and lateral ventricles in human at GW11. Blue arrows, cortical expansion trajectories; red arrows, junction between neocortex and subcortical medial wall. (A) Macaque surface models are reprinted from ref. , which is licensed under CC BY 4.0. (C) Republished with permission of Taylor & Francis Group LLC – Books, from ref. ; permission conveyed through Copyright Clearance Center, Inc.

Fig. 5.

Early-forming cortical sulci in humans. (A and B) Calcarine sulcus at GW13.5 (coronal). (C) “Dimples” in lateral temporal (Top) and medial frontal (Bottom) GW13.5 cortex. (D) Early irregular folds in frontal cortex at GW17. Republished with permission of Taylor & Francis Group LLC – Books, from ref. ; permission conveyed through Copyright Clearance Center, Inc.

Fig. 6.

Schematic of the DES+ model for cerebral cortex. See main text for explanation.

Fig. 7.

Observed and simulated patterns of cortical folding. Starting from the 3D shape of a GW22 human fetal brain, the gel-brain simulation (Top row) and observed anatomical folding pattern (Bottom row) show striking similarities. Reprinted by permission from ref. Springer Nature: Nature Physics, copyright 2016.

Fig. 8.

Cerebellar circuits, development, and morphogenetic forces. (A) Adult cerebellar layers and input/output cell types (interneurons excluded). (B) Schematic of key developmental features at an early developmental stage (∼E17.5 in mouse). (C) Adult mouse parasagittal section drawing, with putative tethering forces provided by input axons.