The gene encoding the mouse contactin‐1 axonal glycoprotein is regulated by the collier/Olf1/EBF family early B‐Cell factor 2 transcription factor

Abstract

The Contactin-1 axonal glycoprotein (formerly F3/Contactin) plays a relevant role in cerebellar ontogenesis, as shown in Contactin-1 KO-mice and in transgenic mice misexpressing the corresponding cDNA from a heterologous promoter. Likewise, null mutant mice for the Collier/Olf1/Early B-cell family transcription factor EBF2, in which Purkinje neuron development is primarily affected, exhibit abnormalities in cerebellar corticogenesis. Here, to evaluate the contribution to the Ebf2 null phenotype of changes in the profile of Contactin-1, we study its expression in Ebf2 null mice. In addition, we explore the activation profile of the Cntn1 gene promoter upon transferring the Ebf2 mutation to transgenic mice expressing an enhanced green fluorescent protein reporter under control of Cntn1 gene regulatory sequences. In Ebf2 null mice, Contactin-1 protein expression and Cntn1 gene promoter activity are both downregulated during embryonic and early postnatal cerebellar development, both in the rostral and caudal folia, while in the latter an upregulation is observed at postnatal day 8. In vitro, vectors driving EBF1,2,3 transcription factors from a cytomegalovirus (CMV) promoter transactivate a Cntn1-Choline acetyltransferse (CAT) promoter-reporter construct in cotransfection assays and, accordingly, by chromatin immunoprecipitation, we show that the Cntn1 gene 5' flanking region is bound by the EBF2 transcription factor, consistent with the evidence that this region bears the cognate deoxyribonucleic acid (DNA) consensus sequences. These data indicate that Contactin-1 expression is dependent upon EBF factors, suggesting that the Cntn1 gene belongs to the expanding regulatory cascade driven by these transcriptional regulators so that changes in its activation may contribute to the phenotype of Ebf2 null mutant mice.

Modulation of Nerve Cell Differentiation: Role of Polyphenols and of Contactin Family Components

“…In the present study, further data arose from the use of an in vivo model consisting in transgenic lines undergoing developmental delay as a consequence of Contactin1 over-expression (Bizzoca et al, 2003, 2012, 2015), in which the consequences were studied of dietary polyphenol administration. The effects of GSP used as a dietary polyphenol source were explored in modulating neurogenesis by using as a model TAG/F3 mice, undergoing Contactin1 over-expression and Notch pathway upregulation, in turn resulting into a neurodevelopmental delay (Bizzoca et al, 2003, 2012).…”

“…Developmental parameters were also studied in vivo in the cerebellar cortex, in which the GSP effects were explored in wild type (WT) or, alternatively, in TAG/F3 transgenic mice, undergoing Contactin1 developmental overexpression under control of the Contactin2 promoter (Bizzoca et al, 2003). The generation and use of this line have been described (Bizzoca et al, 2003, 2012, 2015; Coluccia et al, 2004; Puzzo et al, 2013, 2015). TAG/F3 mice were maintained as heterozygotes and time-pregnant littermates were used throughout, the day of vaginal plug being considered as the embryonic day 0 (E0).…”

“…These studies indicated that differential activation of the underlying genes during either early or, respectively, late ontogenesis may contribute to their specific ontogenetic function. Accordingly, changes in the profiles of such genes may result in morphogenetic consequences in regions provided with different developmental history, including the cerebellar and cerebral cortices (Bizzoca et al, 2003, 2012, 2015), the basal ganglia (Massaro et al, 2012), and the hippocampus (Puzzo et al, 2013, 2015). In addition, these changes may sustain the pathogenesis of specific neurological disorders, typically shown in the case of the autism (Zuko et al, 2011, 2013) and of some dysmyelinating neuropathies (Querol et al, 2013; Manso et al, 2016).…”

Autoantibody profiling reveals four protein candidate autoantigens associated with systemic lupus erythematosus

“…EBF2 is a transcription factor with only partly known functions, such as being a transcriptional determinant of an osteoblastic niche in maintenance of hematopoietic progenitors, partly by modulating Wnt signaling. 27 A role of EBF2 has been described in various fields, even including a role as a highly specific marker of brown fat cells 28 and also a role in nerve system maturation including cerebellum ontogenesis, 29 but a putative role of antibodies to EBF2 in autoimmunity so far is not examined. We found a positive significant association of reactivity to EBF2 with the SLAM index, suggesting that this autoantigen may play a role in the inflammatory process of active SLE disease.…”