Title

 

Authors

A. Massaro¹, A. Bizzoca², P. Corsi², M. Pinto¹, M. Persichella¹, A. Giustino¹, G. Gennarini² and M.R. Carratù^1
 
1Dept. of Biomedical Sciences and Human Oncology, Section of Medical Pharmacology University of Bari “Aldo Moro”, Italy; ²Dept. of Basic Medical Sciences, University of Bari“Aldo Moro”, Italy

 

Abstract

F3/Contactin is a neuronal surface glycoprotein, which plays a relevant role in the control of neural development and in particular in neuronal and oligodendrocyte differentiation (Virgintino et al. 1999; Bizzoca et al. 2009). In this study we demonstrate that downregulation of F3/Contactin expression affects the fate of neuronal populations belonging to the dopaminergic pathway. In preliminary studies, transgenic mice expressing F3/Contactin cDNA or promoter/reporter constructs were screened for the locomotor behaviour. In particular, we found that the F3/EGFP mice, which express an EGFP reporter under control of a selected regulatory region from the mouse F3/Contactin gene, exhibit a locomotor pattern characterized by age-dependent hyperactivity and, surprisingly, by bursts of intense circling behaviour, which recapitulates the one arising from imbalance of the striatal dopaminergic pathway (Löscher 2010; Schirmer et al. 2007). Given that expression of the EGFP reporter is by definition devoid of effects on nervous tissue structure and function we inferred that this phenotype likely results from the ability of transgene promoter sequences to interfere with the activation of the endogenous gene. Indeed, F3/Contactin protein expression appeared to be significantly downregulated in F3/EGFP mice when measured at either the immunohistochemical and biochemical levels, indicating that this transgenic line in fact realizes an F3/Contactin knockdown model. Studying these mice at the morphological and biochemical levels indicated that the dopaminergic differentiation was significantly promoted, as demonstrated through tyrosine hydroxylase expression, significantly increased in the basal ganglia. Moreover, we demonstrated that hyperactivity exhibited by the F3/EGFP mice was responsive to the dopaminergic D₂/D₃ agonist quinpirole, whereas it was unresponsive to the dopaminergic D₃ preferring antagonist nafadotride, thus suggesting a possible misexpression of D₃ receptor subtypes in the transgenic mice with consequent imbalance between D₃ and D₁/D₂ receptor activity. The similar time course of the changes in F3/Contactin and tyrosine hydroxylase expression, and locomotor behaviour indicated that F3/Contactin was normally able to counteract the dopaminergic phenotype.
 
Bizzoca et al. (2009). Cell Adh Migr 3:53-63.
Löscher  (2010). Neurosci Biobehav Rev 34:31-49.
Schirmer et al.(2007).  Neuroscience 144:1462-1469.
Virgintino et al. (1999). J Comp Neurol 413: 357-372