Smad2 Protein Disruption in the Central Nervous System Leads to Aberrant Cerebellar Development and Early Postnatal Ataxia in Mice

Lixiang Wang,Masatoshi Nomura,Yutaka Goto,Kimitaka Tanaka,Ryuichi Sakamoto,Ichiro Abe,Shohei Sakamoto,Atsushi Shibata,Patricio L.M Enciso,Masahiro Adachi,Keizo Ohnaka,Hisaya Kawate,Ryoichi Takayanagi

doi:10.1074/jbc.m111.223271

Lixiang Wang, Masatoshi Nomura + Show 11 more

Open Access

https://doi.org/10.1074/jbc.m111.223271

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Journal: The Journal of biological chemistry	Publication Date: May 1, 2011
Citations: 17	License type: cc-by

Affiliation: Kyushu University

Abstract

Smad2 is a critical mediator of TGF-β signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.

Highlights

Smad2 is a critical mediator of TGF-␤ signals that are known to play an important role in a wide range of biological processes in various cell types
Both Smad2-FL and Smad2-⌬e3 proteins were found in the cerebrum and cerebellum, with Smad2-⌬e3 predominantly expressed in the cerebellum
To determine whether the decrease in the volume and hypoplastic formation of the cerebellum was the result of increased cell death, decreased cell proliferation and/or delayed granule cell maturation and migration, we evaluated whether the Smad2-CNS-KO cerebellum shows abnormal apoptosis, proliferation, and/or maturation and migration

Summary

Introduction

Smad2 is a critical mediator of TGF-␤ signals that are known to play an important role in a wide range of biological processes in various cell types. We report that mice lacking Smad2 in the CNS exhibit ataxic behaviors, abnormal cerebellar foliation, and deficits in granule cell (GC)2 maturation and Purkinje cell (PC) dendritogenesis.

Results

Conclusion