Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum

Abstract

Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of many adult central nervous system (CNS) neurons. These extracellular matrices (ECMs) play a structural role as well as instructive roles in the control of CNS plasticity and the termination of critical periods. The cartilage link protein Crtl1/Hapln1 was reported to be a trigger for the formation of PNNs in the visual cortex. Bral2/Hapln4 is another link protein that is expressed in PNNs, mainly in the brainstem and cerebellum. To assess the role of Bral2 in PNN formation, we examined the expression of PNN components in targeted mouse mutants lacking Bral2. We show here that Bral2-deficient mice have attenuated PNNs, but the overall levels of chondroitin sulfate proteoglycans, lecticans, are unchanged with the exception of neurocan. Bral2 deficiency markedly affected the localization of brevican in all of the nuclei tested, and neurocan concomitant with Crtl1 in some of the nuclei, whereas no effect was seen on aggrecan even with the attenuation of Crtl1. Bral2 may have a role in the organization of the PNN, in association with brevican, that is independent of aggrecan binding. There was a heterogenous attenuation of PNN components, including glycosaminoglycans, indicating the elaborate molecular organization of the PNN components. Strikingly, a slight decrease in the number of synapses in deep cerebellar nuclei neurons was found. Taken together, these results imply that Bral2-brevican interaction may play a key role in synaptic stabilization and the structural integrity of the PNN.

Modifications of perineuronal nets and remodelling of excitatory and inhibitory afferents during vestibular compensation in the adult mouse

“…*P \ 0.05, **P \ 0.01, ***P \ 0.001. Scale bar 15 lm in a (also applies to b-o) neurocan, brevican and phosphacan), hyaluronan, link proteins and semaphorin3A (Brückner et al 2000;Bekku et al 2012;Vo et al 2013;Rácz et al 2014). We found numerous WFA-positive PNNs in the intact ventral LVN, which enwrapped SMI32-positive neurons (87 % of cases; Fig.…”

“…Bral2, together with cartilage link protein-1, is a link protein found in PNNs (Bekku et al 2003(Bekku et al , 2012. Bral2 KO mice display attenuated WFA-bearing PNNs as well as a strong reduction of the PNN component brevican in several nuclei of the brainstem including the LVN (Bekku et al 2012;Fig.…”

“…The absence of link protein-1 in PNN-bearing cells in vitro prevents the formation of a compact surface pericellular matrix ) and knockout mice for link protein-1 exhibit attenuated PNNs throughout the nervous system. In mice lacking Bral2, PNNs appear reduced in several hindbrain areas (Bekku et al 2012).…”

“…The experiments were performed on 3 month-old female FVB, C57BL/6 mice (Harlan, San Pietro al Natisone, Italy) and homozygous Bral2 knockout (KO) mice (Bekku et al 2012). Pax2-GFP transgenic mice were used to visualise GABAergic interneurons (Bouchard et al 2005).…”

Identification of candidate genes for familial early-onset essential tremor

“…Behavioral studies or other phenotypic observations such as tremor have not been described for the BRAL2-deficient mice, but Identification of candidate genes in ET X Liu et al further characterization of these mice in light of our findings is warranted. 60 USP46 was identified as a candidate gene in family E. USP46 belongs to a family of deubiquitinating enzymes that regulate diverse cellular functions by cleaving ubiquitin from specific protein substrates. They have been implicated in a wide variety of biological processes and disease processes including cancer and neurodegenerative disease.…”