β1-Integrins Are Critical for Cerebellar Granule Cell Precursor Proliferation

Abstract

We have previously shown that mice with a CNS restricted knock-out of the integrin ␤1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adult Itgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum of Itgb1-CNSko mice. In the absence of ␤1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that ␤1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on ␤1 integrin expression in GCPs. Taken together, these data are consistent with a model in which ␤1 integrin expression in GCPs is required to recruit a laminin-Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.

Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis

“…Laminin-511 is known to be a major ligand for ␣3␤1 integrin (Kikkawa et al 1998), and previous studies of the deletion of ␣3 integrin have shown severe defects of hair morphogenesis, including altered hair follicle downgrowth. ␤1 integrin has been previously linked to Shh expression in both neural and intestinal tissues (Blaess et al 2004;Jones et al 2006). While prior studies examining the role of ␤1 integrin in hair have focused only on follicular epithelium, not the dermis (Brakebusch et al 2000;Raghavan et al 2000), our present studies suggest that integrins located on dermal cells may play an important role in laminin-511's promotion of hair morphogenesis.…”

β1 Integrins Control the Formation of Cell Chains in the Adult Rostral Migratory Stream

“…␤1 integrins were thought to control cell motility in several of these modes of migration (Clegg et al, 2003), but our findings suggest that ␤1 integrins have a much more specific role than previously appreciated. Our previously published data (Graus-Porta et al, 2001;Blaess et al, 2004) provide strong evidence that many of the migratory events that are important for the development of the cerebral and cerebellar cortex progress normally in the absence of ␤1 integrins. Similarly, although studies with function blocking antibodies have suggested that ␤1 integrins control cell motility of neuroblasts in the RMS, for example by controlling leading process extension (Murase and Horwitz, 2002;Emsley and Hagg, 2003), our data now show that ␤1-deficient neuroblasts in the RMS still elaborate extensive leading processes and are able to migrate directionally toward the OB.…”

Distinct Roles of the β1-Class Integrins at the Developing and the Mature Hippocampal Excitatory Synapse

“…In previous experiments, this conditional allele was introduced into a cre line whose expression is driven by the neuronal enhancer element of the nestin gene promoter. This resulted in deletion of the ␤1 integrin gene throughout much of the nervous system and led to severe developmental defects in cerebral cortical lamination and cerebellar foliation (Graus-Porta et al, 2001;Blaess et al, 2004). To study more specifically the functions of ␤1-class integrins in excitatory neurons, we used another cre line whose expression is driven by the emx1 gene promoter by virtue of an internal ribosome entry site element engineered into the emx1 locus (Gorski et al, 2002).…”