The role of alpha3beta1 integrin in cortical development.

Normal development of the mammalian cerebral cortex requires the coordinated migration of postmitotic neurons from the proliferative ventricular zone to the developing cortical plate.

Of the two main classes of neurons in the cerebral cortex, glutamatergic long projection neurons arise from the ventricular zone of the dorsal telencephalon and migrate radially into the cortical plate.

In contrast, GABAergic interneurons derive primarily from the medial ganglionic eminence in the ventral telencephalon, migrate tangentially into the cortex, and subsequently enter the cortical plate radially using the radial glial scaffold.

Abnormalities in neuronal migration and layer formation lead to abnormal placement and connectivity of cortical neurons, an underlying cause of many congenital brain disorders such as epilepsy, microencephaly (small brain), schizencephaly (split brain hemispheres), lissencephaly (smooth cerebrum, without convolutions), macrogyria (large convolutions), polymicrogyria (small cerebral convolutions), and tuberous sclerosis.

The aim of this dissertation is to elucidate the role of alpha3 integrin in the migration and differentiation of distinct classes of cortical neurons using conditional alpha3 null mouse models.

We find that netrin1-alpha3beta1 integrin interactions promote and maintain the migration of GABAergic interneurons through the cortical marginal zone and, hence, are required for the proper integration of cortical interneurons into the postnatal cerebral cortex.

In addition, the final differentiation of pyramidal neurons and interneurons is dependent on alpha3beta1 integrin signaling during cortical neuronal migration.