Functional characterization and molecular identification of neuroprotective receptors for erythropoietin-like ligands

Hahn, Nina

dc.contributor.advisor	Heinrich, Ralf Prof. Dr.
dc.contributor.author	Hahn, Nina
dc.date.accessioned	2019-12-19T10:27:07Z
dc.date.available	2021-12-12T00:50:03Z
dc.date.issued	2019-12-19
dc.identifier.uri	http://hdl.handle.net/21.11130/00-1735-0000-0005-12D9-2
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-7774
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	570	de
dc.title	Functional characterization and molecular identification of neuroprotective receptors for erythropoietin-like ligands	de
dc.type	cumulativeThesis	de
dc.contributor.referee	Heinrich, Ralf Prof. Dr.
dc.date.examination	2019-12-13
dc.description.abstracteng	The cytokine erythropoietin (Epo) regulates erythropoiesis but also protects mammalian neurons from apoptosis. However, receptors and transduction pathways involved in neuroprotection are only partially characterized. Although insects lack Epo and classical Epo receptor genes, human recombinant Epo induces protection and promotes neuroregeneration of insect neurons. Thus, insect neurons are a suitable model system to study neuroprotective signaling pathways independent from erythropoietic pathways. My studies on insect primary brain neurons demonstrated that recombinant human Epo protects neurons against hypoxia-induced apoptosis by activating orthologs of cytokine receptor like factor 3 (CRLF3), a predicted cytokine receptor with unknown ligand and function in mammals. To this end, I established soaking RNA interference to knock down orthologs of CRLF3 in primary brain cell cultures of the beetle Tribolium castaneum and the locust Locusta migratoria. Furthermore, I tested various Epo-like molecules which have been described in vertebrates to be neuroprotective but not erythropoietic. All tested Epo-like molecules were also neuroprotective in locust primary brain neurons. These shared neuroprotective functions propose that the ligand-binding structures of neuroprotective receptors in insects and vertebrates are more similar than those of the neuroprotective and erythropoietic receptors within vertebrates. Moreover, I provided evidence that neuroprotective effects of the human splice variant EV-3 and an Epo-mimetic peptide are mediated via CRLF3. Phylogenetic analysis of 293 CRLF3 sequences revealed that CRLF3 emerged with the origin of the eumetazoan nervous system. This coincidence suggests that CRLF3 might have originally evolved for a function within the nervous system. However, I have demonstrated CRLF3 expression also in other tissues apart from the nervous system in human cell lines, Tribolium castaneum and Locusta migratoria. In both human neuroblastoma (SH-SY5Y) cells and Tribolium tissue CRLF3 expression is regulated by hypoxic stress. Moreover, I showed that CRLF3 expression is present at all developmental stages of Tribolium but to a variable extent. In this study, I tested the hypothesis that CRLF3 might be a neuroprotective Epo receptor. The results presented herein show that CRLF3 is crucial to mediate the neuroprotective effect of human Epo and Epo-like cell protective molecules in insect primary brain cells. Whether this function of CRLF3 is also present in human brain cells has to be proven in future experiments for which I have already established pivotal tools. This study introducing CRLF3 as a neuroprotective Epo receptor might support the development of safe, neuroprotective therapies that selectively stimulate CRLF3.	de
dc.contributor.coReferee	Bucher, Gregor Prof. Dr.
dc.contributor.thirdReferee	Bradler, Sven Dr.
dc.contributor.thirdReferee	Posnien, Nico Dr.
dc.contributor.thirdReferee	Schmidt, Manuela Prof. Dr.
dc.contributor.thirdReferee	Werner, Hauke Dr.
dc.subject.eng	Neuroprotection	de
dc.subject.eng	Erythropoietin	de
dc.subject.eng	CRLF3	de
dc.subject.eng	Cytokine receptor-like factor 3	de
dc.subject.eng	Orphan cytokine receptor	de
dc.subject.eng	Neurodegenerativ diseases	de
dc.subject.eng	Tribolium castaneum	de
dc.subject.eng	Soaking RNAi	de
dc.subject.eng	Locusta migratoria	de
dc.subject.eng	Epo	de
dc.subject.eng	Nervous system	de
dc.subject.eng	Evolution	de
dc.identifier.urn	urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-12D9-2-2
dc.affiliation.institute	Biologische Fakultät für Biologie und Psychologie	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.description.embargoed	2021-12-12
dc.identifier.ppn	1686132441

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