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doi: 10.1242/10.1242/dev.00183

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Transgenic mice expressing F3/contactin from the TAG-1 promoter exhibit developmentally regulated changes in the differentiation of cerebellar neurons

Antonella Bizzoca¹, Daniela Virgintino², Loredana Lorusso¹, Maura Buttiglione¹, Lynn Yoshida⁵, Angela Polizzi¹, Maria Tattoli¹, Raffaele Cagiano¹, Ferdinando Rossi³, Serguei Kozlov^4,*, Andrew Furley^5, and Gianfranco Gennarini^1,

¹ Dipartimento di Farmacologia e Fisiologia Umana, Università di Bari; Università di Torino, Italy
² Dipartimento di Anatomia Umana ed Istologia, Università di Bari; Università di Torino, Italy
³ Università di Bari; Dipartimento di Neuroscienze, Università di Torino, Italy
⁴ Institute of Biochemistry, University of Zurich, Switzerland
⁵ Centre for Developmental Genetics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK
^* Present address: Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA

Authors for correspondence (e-mail: G.Gennarini{at}tno.it and A.J.Furley@Sheffield.ac.uk)

Accepted 3 October 2002

F3/contactin (CNTN1) and TAG-1 (CNTN2) are closely related axonal glycoproteins that are differentially regulated during development. In the cerebellar cortex TAG-1 is expressed first as granule cell progenitors differentiate in the premigratory zone of the external germinal layer. However, as these cells begin radial migration, TAG-1 is replaced by F3/contactin. To address the significance of this differential regulation, we have generated transgenic mice in which F3/contactin expression is driven by TAG-1 gene regulatory sequences, which results in premature expression of F3/contactin in granule cells. These animals (TAG/F3 mice) display a developmentally regulated cerebellar phenotype in which the size of the cerebellum is markedly reduced during the first two postnatal weeks but subsequently recovers. This is due in part to a reduction in the number of granule cells, most evident in the external germinal layer at postnatal day 3 and in the inner granular layer between postnatal days 8 and 11. The reduction in granule cell number is accompanied by a decrease in precursor granule cell proliferation at postnatal day 3, followed by an increase in the number of cycling cells at postnatal day 8. In the same developmental window the size of the molecular layer is markedly reduced and Purkinje cell dendrites fail to elaborate normally. These data are consistent with a model in which deployment of F3/contactin on granule cells affects proliferation and differentiation of these neurons as well as the differentiation of their synaptic partners, the Purkinje cells. Together, these findings indicate that precise spatio-temporal regulation of TAG-1 and F3/contactin expression is critical for normal cerebellar morphogenesis.

Key words: Cerebellar development, Neurite growth, Axonal glycoproteins, F3/contactin, TAG-1, Gene regulation, Cell proliferation, Mouse

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