6814 • The Journal of Neuroscience, July 19, 2017 • 37(29):6814–6815 Journal Club Editor’s Note: These short reviews of recent JNeurosci articles, written exclusively by students or postdoctoral fellows, summarize the important findings of the paper and provide additional insight and commentary. If the authors of the highlighted article have written a response to the Journal Club, the response can be found by viewing the Journal Club at www.jneurosci.org. For more information on the format, review process, and purpose of Journal Club articles, please see http://jneurosci.org/content/ preparing-manuscript#journalclub. Relevance of the Proteolytic Processing of Reelin by ADAMTS-3 in Brain Functions Sighild Lemarchant Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 5287, Bordeaux University, 33076 Bordeaux Cedex, France Review of Ogino et al. Reelin is a prominent extracellular glyco- restore brain functions in these pathological volved: NR2 (from NTR to RR2) and protein that has roles in the CNS through- conditions. R78C (from RR7 to the CTR) fragments, out development and maturity. During Reelin binds to the apolipoprotein E but also three fragments containing the development, Reelin is produced by Cajal- receptor 2 and the very low-density lipopro- receptor binding region: for instance, Retzius cells at the marginal zone above the tein receptor, and this triggers phospho- NR6 (from NTR to RR6), R36 (from RR3 cortical plate and by granule cells in the rylation of the cytosolic adaptor protein to RR6), and R38C (from RR3 to the cerebellum, and it controls cytoskeletal disabled-1 (Dab-1) by kinases of the Src CTR) fragments (Koie et al., 2014; Sato et dynamics required for the laminar migra- family, which promotes the activation of al., 2016). Which protease is involved in tion of neurons, and remodeling of den- downstream signaling. Reelin-Dab-1 sig- Reelin cleavage and how cleavage at these drites and spines. In the mature brain, naling leads to the phosphorylation and sites affects Reelin function remains elu- GABAergic interneurons and glutamater- subsequent inactivation of glycogen syn- sive. Whereas some reports indicate that gic pyramidal neurons in layer II of the thase kinase-3␤. Ultimately, the decrease the N-terminal cleavage of Reelin entorhinal cortex take over the produc- of glycogen synthase kinase-3␤ activity promotes the conversion of “inactive” full- tion of Reelin, which continues to regulate prevents excessive phosphorylation of length Reelin into an “active” fragment (Jos- neuronal function and synaptic activity the microtubule-associated protein Tau, sin et al., 2007; Tinnes et al., 2013), a (Knuesel et al., 2009). During aging, re- thereby preserving neuronal integrity, growing body of evidence also shows that duction of Reelin expression contributes axonal transport, and synaptic plasticity the N-terminal cleavage of Reelin negatively to synaptic plasticity defects and cognitive (Doehner and Knuesel, 2010; Guo et al., modulates Reelin function in neuron cul- impairments (Doehner and Knuesel, 2010). 2017). Phosphorylated Dab-1 is then de- tures (Kohno et al., 2009; Koie et al., 2014; A decrease in Reelin activity also contributes graded via the ubiquitin-proteasome Ogino et al., 2017). In a study recently pub- to pathogenesis and/or deterioration in pathway, which ensures a fine-tuning of lished in The Journal of Neuroscience, Ogino several neuropsychiatric and neurodegen- the Reelin response (Arnaud et al., 2003). et al. (2017) identified a key protease that erative disorders, including schizophrenia, Full-length Reelin is composed of an cleaves Reelin, and they show that cleavage frontotemporal dementia, and Alzheimer’s N-terminal region (NTR), eight Reelin by this protease inactivates Reelin. disease. Therefore, developing therapeutic repeats (RRs), and a C-terminal region By using chromatography and mass strategies to increase Reelin activity might (CTR). The central region (RR3-RR6) is spectrometry, Ogino et al. (2017) discov- required for receptor binding, and the ered that N-terminal cleavage of Reelin in NTR and CTR are responsible for Reelin primary cultures of neurons was achieved Received April 21, 2017; revised June 8, 2017; accepted June 16, 2017. multimerization and folding, respectively. by the metalloproteinase ADAMTS-3 (type 3 S.L. was supported by the Era-Net Neuron TRAINS (time-dependent remote alterations after injury to the nervous system). After secretion in the extracellular space, a disintegrin and metalloproteinase with The author declares no competing financial interests. Reelin is subject to specific proteolytic thrombospondin motifs). This result was Correspondence should be addressed to Dr. Sighild Lemarchant, Centre cleavage at RR3 (Pro1244-Ala1245) (N- confirmed by the abolishment of the National de la Recherche Scientifique, Unite´ Mixte de Recherche 5287, terminal cleavage) and/or between RR6 N-terminal cleavage in the culture media Bordeaux University, 146 rue Le´o Saignat, 33076 Bordeaux Cedex, France. E-mail: [email protected]. and RR7 (Ala2688-Asp2689) (C-terminal of ADAMTS-3 knock-out (KO) neurons. DOI:10.1523/JNEUROSCI.1077-17.2017 cleavage). This can generate five frag- Importantly, the authors showed that the Copyright © 2017 the authors 0270-6474/17/376814-02$15.00/0 ments depending on the protease in- expression of ADAMTS-3 in mouse em- Lemarchant • Journal Club J. Neurosci., July 19, 2017 • 37(29):6814–6815 • 6815 bryos and adults greatly overlaps with the in line with several studies reporting the signaling during normal and pathological expression of neurons targeted by Reelin. dendritic remodeling of excitatory neu- forms of aging. Aging Dis 1:12–29. Medline For instance, hybridization revealed the rons by Reelin (Niu et al., 2008; Chameau Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuro- presence of ADAMTS-3 in TBR1-positive et al., 2009). Considering the importance pathol 133:665–704. CrossRef Medline neurons present in the deep cortical plate of spine modeling by Reelin and its impact Iafrati J, Orejarena MJ, Lassalle O, Bouamrane L, as well as in upper cortical layers. In adults, on LTP in the prefrontal cortex of juvenile Gonzalez-Campo C, Chavis P (2014) Reelin, the expression of ADAMTS-3 was wide- mice (Iafrati et al., 2014), it would have an extracellular matrix protein linked to early spread throughout the brain, including in been valuable to look at dendritic spine onset psychiatric diseases, drives postnatal de- the cerebellum and in the cortex. Thus, density in ADAMTS-3 cKO mice. velopment of the prefrontal cortex via GluN2B- ADAMTS-3 is expressed in regions where The proteolysis of Reelin by ADAMTS-3 NMDARs and the mTOR pathway. Mol Psychiatry 19:417–426. CrossRef Medline it may process Reelin in vivo. might be a decisive upstream molecular Jossin Y, Gui L, Goffinet AM (2007) Processing Ogino et al. (2017) next looked at the mechanism leading to Reelin inactivation, of Reelin by embryonic neurons is important expression of Reelin and its intracellular which may contribute to and/or worsen for function in tissue but not in dissociated effectors in the cerebral cortex of wild- the pathogenesis of neuropsychiatric and cultured neurons. J Neurosci 27:4243–4252. type and ADAMTS-3 KO mice during neurodegenerative disorders. Previous studies CrossRef Medline embryonic development. At embryonic have shown that several proteases, including Knuesel I, Nyffeler M, Morme`de C, Muhia M, day 13.5 and 16.5, levels of NR6 were in- ␣ ␤ Meyer U, Pietropaolo S, Yee BK, Pryce CR, tissue plasminogen activator, meprin and , LaFerla FM, Marighetto A, Feldon J (2009) creased, whereas levels of NR2 were de- matrix metalloproteinase-9, and ADAMTS-4 Age-related accumulation of Reelin in amyloid- creased. This apparent reduction of the and -5 can cleave Reelin (Krstic et al., like deposits. Neurobiol Aging 30:697–716. N-terminal cleavage of Reelin in ADAMTS-3 2012; Lussier et al., 2016; Sato et al., 2016), CrossRef Medline KO mice increased activation of Reelin- but ADAMTS-3 KO mice are the only KO Kohno S, Kohno T, Nakano Y, Suzuki K, Ishii M, Dab-1 signaling as indicated by Dab-1 mice in which altered levels of Reelin have Tagami H, Baba A, Hattori M (2009) Mech- degradation and decreased levels of phos- been documented. Thus, abnormal acti- anism and significance of specific proteolytic cleavage of Reelin. Biochem Biophys Res phorylated Tau in these mice. Surpris- vation of ADAMTS-3-Reelin signaling Commun 380:93–97. CrossRef Medline ingly, these changes in ADAMTS-3 KO might prevent spine development and Koie M, Okumura K, Hisanaga A, Kamei T, Sasaki mice did not alter the positioning of radi- LTP in the postnatal brain and contribute K, Deng M, Baba A, Kohno T, Hattori M ally migrating neurons, suggesting that to the development and/or deterioration (2014) Cleavage within Reelin repeat 3 regu- the NTR is not required for the laminar of neuropsychiatric disorders, such as lates the duration and range of the signaling migration of neurons. Nevertheless, schizophrenia. It may also promote Tau activity of Reelin protein. J Biol Chem 289: ϳ25%–40% of NR2 fragments were still hyperphosphorylation and aggregation, 12922–12930. CrossRef Medline Krstic D, Rodriguez M, Knuesel I (2012) Regu- present in the cortex of ADAMTS-3 KO em- and the subsequent formation of neuro- lated proteolytic processing of Reelin through bryos, suggesting that (1) ADAMTS-3 KO fibrillary tangles in Alzheimer’s disease interplay of tissue plasminogen activator (tPA), mice might show compensatory upregu- (Guo et al., 2017). Therefore, the develop- ADAMTS-4, ADAMTS-5, and their modula- lation of other proteases that cleave Ree- ment of monoclonal antibodies or specific tors. PLoS One 7:e47793. CrossRef Medline lin, (2) ADAMTS-3 might not be the only inhibitors targeting ADAMTS-3 may lead Lussier AL, Weeber EJ, Rebeck GW (2016) Ree- protease cleaving Reelin in vivo, or (3) an- to innovative therapeutic strategies to lin proteolysis affects signaling related to nor- other protease controls the laminar mi- mal synapse function and neurodegeneration.