Cell‐specific and developmental expression of lectican‐cleaving proteases in mouse hippocampus and neocortex

Abstract

Mounting evidence has demonstrated that a specialized extracellular matrix exists in the mammalian brain, and this glycoprotein-rich matrix contributes to many aspects of brain development and function. The most prominent supramolecular assembly of these ECM glycoproteins are perineuronal nets, specialized lattice-like structures that surround the cell bodies and proximal neurites of select classes of interneurons. Perineuronal nets are composed of lecticans – a family of chondroitin sulfate proteoglycans [CSPGs] that includes aggrecan, brevican, neurocan, and versican. The presence of these lattice-like structures emerge late in postnatal brain development and coincides with the ending of critical periods of brain development. Despite our knowledge of the presence of lecticans in perineuronal nets and their importance in regulating synaptic plasticity, we know little about the development or distribution of extracellular proteases that are responsible for their cleavage and turnover. A subset of the large “A Disintegrin and Metalloproteinase with Thrombospondin Motifs” (ADAMTS) family of extracellular proteases is responsible for endogenously cleaving lecticans. We therefore explored the expression pattern of 2 aggrecan-degrading ADAMTS family members, ADAMTS15 and ADAMTS4, in hippocampus and neocortex. Here, we show that both lectican-degrading metalloproteases are present in these brain regions and each exhibits a distinct temporal and spatial expression pattern. Adamts15 mRNA is expressed exclusively by Parvalbumin-expressing interneurons during synaptogenesis, whereas, Adamts4 mRNA is exclusively generated by telencephalic oligodendrocytes during myelination. Thus, ADAMTS15 and ADAMTS4 not only exhibit unique cellular expression patterns but their developmental upregulation by these cell types coincides with critical aspects of neural development.

ADAMTS‐4 in oligodendrocytes contributes to myelination with an impact on motor function

“…Our data revealed ADAMTS‐4 as present in the white matter of the CNS, only in mature APC positive oligodendrocytes. These data are in agreement with recent studies that have reported the expression of ADAMTS‐4 in mature oligodendrocytes by in situ hybridization in the developing telencephalon (Levy, Brooks, Chen, Su, & Fox, ) and by immunohistochemistry of adult mouse spinal cord (Lemarchant, Pomeshchik, et al, ). Notably, ADAMTS‐4 protein was recently described as highly enriched in oligodendrocytes by a proteomic analysis (Sharma et al, ), among the well‐known oligodendrocytes proteins such as MBP, PLP, 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase and the transcription factor Sox10.…”

“…The major finding of our present study is that the extracellular ADAMTS-4, initially characterized in the cartilage (Tortorella et al, 1999) is exclusively expressed by myelinating oligodendrocytes in the normal CNS, influences myelination processes, axonal conduction and finally motor performances. (Levy, Brooks, Chen, Su, & Fox, 2015) and by immunohistochemistry of adult mouse spinal cord . Notably, ADAMTS-4 protein was recently described as highly enriched in oligodendrocytes by a proteomic analysis (Sharma et al, 2015), among the well-known oligodendrocytes proteins such as MBP, PLP, 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase and the transcription factor Sox10.…”

Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning

“…Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) as well as the closely related ‘A Disintegrin and Metalloprotease’ (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs), all of which are involved in ECM proteolysis (Arpino et al, 2015; Levy et al, 2015; Pizzi and Crowe, 2007; Seals and Courtneidge, 2003; Senkov et al, 2014). Therefore, PNN stability in response to Pavlovian fear conditioning could be influenced by the activity and expression of these enzymes.…”

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…However, several previous studies had also strongly suggested that ADAMTS4 could be an oligodendrocyte-specific gene. First, an in situ hybridization study had detected ADAMTS4 mRNA specifically in oligodendrocytes of the mouse hippocampus and cortex at P21, and in co-localization studies the riboprobe only bound to cells positive for the oligodendrocyte marker Olig2 [44]. Second, a state-of-the-art transcriptome study of all major brain cell types had indicated that ADAMTS4 is specifically expressed in oligodendrocytes [82].…”