Beta1-integrins are critical for cerebellar granule cell precursor proliferation.
We have previously shown that mice with a CNS restricted knock-out of the integrin beta1 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 beta1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that beta1 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 beta1 integrin expression in GCPs. Taken together, these data are consistent with a model in which beta1 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.
Blaess
Sandra
S
Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
Graus-Porta
Diana
D
Belvindrah
Richard
R
Radakovits
Randor
R
Pons
Sebastian
S
Littlewood-Evans
Amanda
A
Senften
Mathias
M
Guo
Huailian
H
Li
Yuqing
Y
Miner
Jeffrey H
JH
Reichardt
Louis F
LF
Müller
Ulrich
U
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005109:Extracellular Matrix / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting / Q000379:methods; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D019426:Integrases; D019012:Integrin beta1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014764:Viral Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D006133:Growth Substances; D053823:Hedgehog Proteins; D019012:Integrin beta1; D007797:Laminin; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C121346:laminin 1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C045073:Cre recombinase; D019426:Integrases