Effects of FAK ablation on cerebellar foliation, Bergmann glia positioning and climbing fiber territory on Purkinje cells

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is widely expressed in the brain, and plays key roles in various cellular processes in response to both extracellular and intracellular stimuli. Here, we explored the role of FAK in cerebellar development. In the mouse cerebellum, FAK was found to be distributed as tiny cytoplasmic aggregates in various neuronal and glial elements, including Purkinje cells (PCs), Bergmann glia (BG), parallel fiber (PF)-terminals and climbing fiber (CF)-terminals. The neuron/glia-specific ablation of FAK impaired cerebellar foliation, such as variable decreases in foliation sizes and the lack of intercrural and precentral fissures. Some of the BG cells became situated ectopically in the molecular layer. Furthermore, the FAK ablation altered the innervation territories of CFs and PFs on PCs. CF innervation regressed to the basal portion of proximal dendrites and somata, whereas ectopic spines protruded from proximal dendrites and PFs expanded their territory by innervating the ectopic spines. Furthermore, the persistence of surplus CFs innervating PC somata caused multiple innervation. When FAK was selectively ablated in PCs, diminished dendritic innervation and persistent somatic innervation by CFs were observed, whereas cerebellar foliation and cell positioning of BG were normally retained. These results suggest that FAK in various neuronal and glial elements is required for the formation of normal histoarchitecture and cytoarchitecture in the cerebellum, and for the construction of proper innervation territory and synaptic wiring in PCs.

Ade novoX;8 translocation creates aPTK2-THOC2gene fusion withTHOC2expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia

“…Purkinje cells from homozygous conditional knockout mice show a normal phenotype22; (c) kin-32 ( PTK2 ortholog) silencing in C. elegans did not affect viability, development, fertility, locomotion and chemosensory activity.…”

Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth

“…In particular, axons lacking FAK extend more slowly than normal (Rico et al, 2004). To investigate the function of FAK in vivo, we generated pyramidal cell-specific conditional Fak mutants by crossing NEX-Cre mice (Goebbels et al, 2006) (Beggs et al, 2003;Rico et al, 2004;Watanabe et al, 2008), we found that loss of Fak function in pyramidal cells did not alter the gross morphology of the cerebral cortex (data not shown). To test the role of FAK in axonal development, we focused on the hippocampal commissural projection.…”

Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum

“…The molecular mechanisms that regulate CF synaptogenesis and fine tuning are not well understood. The GluRδ2, which probably acts as an adhesion molecule (41,42), P/Q-type voltage-dependent Ca 2+ channels, insulin-like growth factor (IGF), focal adhesion kinase (FAK), tyrosine-related kinase B (TrkB), myosinVa, glutamate transporter GLAST, a novel brain specific receptor-like protein family BSRP, mGluR1, the α subunit of the Gq subtype of GTP-binding protein, phospholipase Cβ4, and PKCγ were shown to play roles for the development of CF and PC connectivity (42)(43)(44)(45)(46). PKCγ, which has been shown to be activated by Nogo-A (47) was down-regulated in Nogo-A KO and doubled in L7-Nogo-A TG mice, but its role in PC dendritic tree development seems rather complex (23,48) and a possible role of this pathway for the observed effects of Nogo-A remains to be studied in detail.…”