Atypical Mouse Cerebellar Development Is Caused by Ectopic Expression of the Forkhead Box Transcription Factor HNF-3

Authors: ZHOU H.¹; HUGHES D.E.¹; MAJOR M.L.¹; YOO K.¹; PESOLD C.²; COSTA R.H.¹

Source: Gene Expression, Volume 9, Numbers 4-5, 2001 , pp. 217-236(20)

Publisher: Cognizant Communication Corporation

Abstract:

To assess the role of hepatocyte nuclear factor-3 (HNF-3) 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-3 expression. During breeding of the TTR-HNF-3 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-3 disrupted cerebellar morphogenesis and caused reduction in cerebellar size. In postnatal cerebellum, the HNF-3 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.

Keywords: Cerebellar expression Transgenic mice Winged helix

Language: English

Document Type: Research article

Affiliations: 1: *Department of Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60607 2: ‡The Psychiatric Institute, University of Illinois at Chicago, College of Medicine, Chicago, IL 60607

Publication date: 2001-01-01

• The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
  The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

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• In this Subject: Biotechnology ,  Genetics
• By this author: ZHOU H. ;  HUGHES D.E. ;  MAJOR M.L. ;  YOO K. ;  PESOLD C. ;  COSTA R.H.

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