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.

Induction of Protein Deletion Through <em>In Utero</em> Electroporation to Define Deficits in Neuronal Migration in Transgenic Models

“…Neuronal migration is a highly complex process that is regulated by a multitude of interconnected mechanisms [1][2][3] . As it is very difficult to identify the mechanism underlying a migration defect in an uncharacterized transgenic model, distinguishing cell autonomous versus non-cell autonomous defects can facilitate phenotype characterization.…”

“…It depends on a variety of cell autonomous factors, such as correct mitotic exit and neuronal differentiation, cell polarity, regulation of cytoskeletal dynamics and expression of transmembrane receptors, as well as noncell autonomous factors, such as formation of the radial glial scaffold and secretion of migratory guidance molecules [1][2][3] . Since disruption of any of these mechanisms can impair neuronal migration in a transgenic mouse model [4][5][6][7][8] , determining the underlying cause of a defect in migration can be a complex and difficult process.…”

A balancing Akt: How to fine-tune neuronal migration speed

“…The cell then repeats this series of steps and move forward in a saltatory manner. 7,14,32 Given that centrosome-nucleus coupling is regulated by several genes that are mutated in human neurological diseases, the underlying molecular mechanisms have been studied extensively. For example, Lis1, the product of a gene mutated in lissencephaly, and its associated proteins regulate forward movement of the centrosome away from the nucleus as well as pulling of the nucleus toward the centrosome by cytoplasmic dynein, a motor protein that directs transport toward the minus end of microtubules.…”

“…For example, Lis1, the product of a gene mutated in lissencephaly, and its associated proteins regulate forward movement of the centrosome away from the nucleus as well as pulling of the nucleus toward the centrosome by cytoplasmic dynein, a motor protein that directs transport toward the minus end of microtubules. 7,14,32,49 However, the molecular mechanism underlying centrosome-nucleus coupling is not fully understood.…”

“…Previous studies have revealed molecules and mechanisms controlling contiguous steps of neuronal migration as well as diseases associated with their impairment. 8,14,19,25,28,38 Importantly, there is a precise relation between the temporal order in which the various neuronal cell types are generated and their spatial distribution in the neocortex. 2,4,43,48 Also, cortical neurons utilize multiple modes of migration as described above, and each mode exhibits distinct speed when neurons are migrating through the cortex.…”