Integrative mechanisms of oriented neuronal migration in the developing brain

Abstract

The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization.

Figure 1

Neuronal migration in the developing cerebral cortex. (a) Projection neurons ( pink) and interneurons (blue) originate from distinct proliferative domains and migrate into the developing cerebral wall. (b) Projection neurons, generated from radial glial progenitors (RGPs, brown) or intermediate precursors (IPs, orange), migrate using either radial-glial-independent somal translocation or glial-guided locomotion. Newborn neurons undergo a multipolar transition phase prior to glial-guided radial migration. (c) Interneurons migrate in multiple streams into the pallium. They extend multiple leading branches ➀, followed by branch stabilization ➁, centrosomal movement ➂, ➃, and forward nucleokinesis ➄. (d ) Radially migrating neurons (magenta) and tangentially migrating interneurons ( green) in the E14.5 mouse cerebral wall. (e) Coordinated migration of these neurons during development leads to the laminar organization of neurons in the cerebral cortex. Neurons in different layers of postnatal day 0 cortex are labeled with antibodies to Ctip2 (blue, layer V), Cux1 (red, layers II–IV), Brn1 ( green, layers II–V), and Tbr1 (magenta, layer VI). Adapted from Higginbotham et al. (2012). Abbreviations: CP, cortical plate; IZ, intermediate zone; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; MZ, marginal zone; OSVZ, outer subventricular zone progenitor; Str, striatum; SVZ, subventricular zone; VZ, ventricular zone.

Figure 2

Molecular control of neuronal migration in the developing cerebral cortex. Radially and tangentially migrating neurons are shown in pink and blue, respectively. Molecules known to regulate radial, tangential, or both modes of neuronal migration are indicated in pink, blue, and purple, respectively. Molecules regulating the switch from tangential to radial mode of migration of interneurons are indicated in orange. Regulators of multipolar-to-radial transition of projection neurons are indicated in green. Abbreviations: AM, adhesion molecules; C, connexins; CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SVZ, subventricular zone; VZ, ventricular zone.