Atypical mouse cerebellar development is caused by ectopic expression of the forkhead box transcription factor HNF-3beta.
To assess the role of hepatocyte nuclear factor-3beta (HNF-3beta) in hepatocyte-specific gene transcription, we reported the characterization of the liver phenotype with transgenic mice in which the -3-kb transthyretin (TTR) promoter functioned to increase HNF-3beta expression. During breeding of the TTR-HNF-3beta transgenic mice we noticed that they displayed severe ataxia. In this study, we describe the analysis of our transgenic cerebellar phenotype and demonstrate that ectopic expression of HNF-3beta disrupted cerebellar morphogenesis and caused reduction in cerebellar size. In postnatal cerebellum, the HNF-3beta transgene expression pattern is colocalized to glial fibrillary acidic protein-positive cerebellar astrocytes and Bergmann glial cells. As a result of protracted expression, the transgenic cerebella are impaired in terms of astrocyte dispersal and formation of Bergmann glial cell processes. This caused a disruption in neuronal cell migration to the cortical laminar layers and Purkinje dendritic arbor maturation, thus leading to diminished foliation. Differential hybridization of cDNA arrays was used to identify altered expression of cerebellar genes, which is consistent with the observed defect in transgenic cerebellar morphogenesis and size as well as glial maturation. These include diminished expression of the brain lipid-binding protein, which is required for glial morphological differentiation, and the basic helix-loop-helix NeuroD/Beta2 and homeodomain Engrailed-2 transcription factors, which are required for normal cerebellar morphogenesis and foliation. Undetectable levels of ataxia telangiectasia (ATM), which is required for proper development of the Purkinje dendritic arbor, were found in postnatal transgenic cerebella. Furthermore, the transgenic cerebella displayed levels of insulin-like growth factor binding protein-1 elevated to 22 times greater than those measured for wild-type cerebella, an elevation consistent with the reduction in transgenic cerebellar size.
Zhou
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Department of Molecular Genetics, University of Illinois at Chicago, College of Medicine, 60607, USA.
Hughes
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DE
Major
M L
ML
Yoo
K
K
Pesold
C
C
Costa
R H
RH
D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement; D002531:Cerebellum / Q000002:abnormalities / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D015870:Gene Expression; D005819:Genetic Markers / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta; D017403:In Situ Hybridization; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D039482:Integrin alpha5; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D014157:Transcription Factors / Q000235:genetics
D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D051542:Hepatocyte Nuclear Factor 3-beta; D018970:Insulin-Like Growth Factor Binding Protein 1; D039482:Integrin alpha5; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D066247:Receptor, ErbB-4; D017475:Receptors, Nerve Growth Factor; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D014157:Transcription Factors; C500943:Atoh1 protein, mouse; C496503:Foxa2 protein, mouse; C105653:Unc5c protein, mouse; C587690:Erbb4 protein, mouse