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Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    in photoreceptor degeneration, assessing the activation pattern of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010dependent calpain proteases, generating spatiotemporal maps of the entire retina in the\n                    <jats:italic>cpfl1<\/jats:italic>\n                    mouse model for primary cone degeneration, and in the\n                    <jats:italic>rd1<\/jats:italic>\n                    and\n                    <jats:italic>rd10<\/jats:italic>\n                    models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the\n                    <jats:italic>rd1<\/jats:italic>\n                    and\n                    <jats:italic>rd10<\/jats:italic>\n                    models, spatiotemporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain\u20102 isoform but not with calpain\u20101, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis\u2010inducing factor, although only a minute fraction of cells showed activity of the apoptotic marker caspase\u20103. After primary rod degeneration concluded, caspase\u20103 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggest a causal link between Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dysregulation and primary, nonapoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.\n                  <\/jats:p>","DOI":"10.1002\/cne.24807","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T13:34:35Z","timestamp":1573479275000},"page":"1113-1139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Systematic spatiotemporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration"],"prefix":"10.1002","volume":"528","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-6454","authenticated-orcid":false,"given":"Michael J.","family":"Power","sequence":"first","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Centre for Integrative Neuroscience (CIN) University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Graduate Training Centre of Neuroscience (GTC) University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke E.","family":"Rogerson","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Centre for Integrative Neuroscience (CIN) University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Graduate Training Centre of Neuroscience (GTC) University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Bernstein Center for Computational Neuroscience  T\u00fcbingen Germany"},{"name":"Institute for Bioinformatics and Medical Informatics University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timm","family":"Schubert","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Centre for Integrative Neuroscience (CIN) University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Berens","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Centre for Integrative Neuroscience (CIN) University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Bernstein Center for Computational Neuroscience  T\u00fcbingen Germany"},{"name":"Institute for Bioinformatics and Medical Informatics University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Euler","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Centre for Integrative Neuroscience (CIN) University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Bernstein Center for Computational Neuroscience  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Paquet\u2010Durand","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","unstructured":"Adams R. 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