Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development.
Integrin-linked kinase (ILK) is a serine/threonine protein kinase that plays an important role in integrin signaling and cell proliferation. We used Cre recombinase (Cre)-loxP technology to study CNS restricted knock-out of the ilk gene by either Nestin-driven or gfap-driven Cre-mediated recombination. Developmental changes in ilk-excised brain regions are similar to those observed in mice lacking the integrin beta1 subunit in the CNS, including defective laminin deposition, abnormal glial morphology, and alterations in granule cell migration. Decreases in 6-bromodeoxyuridine (BrdU) pulse labeling and proliferating cell nuclear antigen expression in the external granule cell layer of the cerebellum demonstrated that proliferation is disrupted in granule cells lacking ILK. Previous studies have shown that laminin-sonic hedgehog (Shh)-induced granule cell precursor (GCP) proliferation is dependent on beta1 integrins, several of which bind laminin and interact with ILK through the beta1 cytoplasmic domain. Both ex vivo deletion of ilk and a small molecule inhibitor of ILK kinase activity decreased laminin-Shh-induced BrdU labeling in cultured GCPs. Together, these results implicate ILK as a critical effector in a signaling pathway necessary for granule cell proliferation and cerebellar development.
Mills
Julia
J
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada.
Niewmierzycka
Agnieszka
A
Oloumi
Arusha
A
Rico
Beatriz
B
St-Arnaud
Rene
R
Mackenzie
Ian R
IR
Mawji
Nasrin M
NM
Wilson
Jason
J
Reichardt
Louis F
LF
Dedhar
Shoukat
S
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000201:enzymology* / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology*; D000099200:Scaffold Protein ILK
D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK