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@ARTICLE{Butt:285264,
author = {Butt, Umer Javed and Çakır, Umut and Wildenburg,
Anne-Fleur and Curto, Yasmina and Ye, Liu and Bansal, Vikas
and Boretius, Susann and Nave, Klaus-Armin and Singh,
Manvendra and Ehrenreich, Hannelore},
title = {{F}orebrain-specific loss of erythropoietin provokes
compensatory upregulation of different {EPO} receptors.},
journal = {Molecular psychiatry},
volume = {31},
number = {3},
issn = {1359-4184},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2026-00206},
pages = {1241 - 1252},
year = {2026},
abstract = {The procognitive growth factor erythropoietin (EPO) and its
canonical receptor, EPOR, have long been recognized to be
expressed by most cell types in the brain. Cognitive
domains, improved by injections of exogenous EPO or by
endogenous, hypoxia-stimulated EPO, include important
forebrain functions, namely attention, working memory,
drive, and executive performance. To gain mechanistic
insight into the involvement of forebrain-expressed EPO, we
deleted EPO in mice using as specific cre-driver Emx1. Here,
we report that these mutant mice act comparably to their
wildtype littermates in a comprehensive behavioral test
battery. Importantly, we find that the transcripts of both
EPOR and a novel, brain-expressed EPO receptor, EphB4,
respond to EPO deletion with compensatory upregulation.
EphB4 expression in brain and its increase upon forebrain
erasure of EPOR are confirmed by in situ hybridization and
immunohistochemistry. The augmented expression of both EPOR
and EphB4 and their regulatory intercorrelation may explain
why EmxEPO mutants show an even superior performance in the
most challenging working memory task. Using the previously
published single-nuclei-RNA-seq dataset, we further confirm
the suggested compensatory mechanism, wherein EPO loss or
reduction drives elevated EPOR expression, adding another
layer to the intricate regulation of EPO signaling in
hippocampal pyramidal neurons. Collectively, these data may
explain the lack of behavioral and negative cognitive
consequences upon forebrain-wide EPO elimination.},
keywords = {Animals / Erythropoietin: metabolism / Erythropoietin:
genetics / Prosencephalon: metabolism / Receptors,
Erythropoietin: metabolism / Receptors, Erythropoietin:
genetics / Mice / Memory, Short-Term: physiology /
Up-Regulation / Receptor, EphB4: metabolism / Receptor,
EphB4: genetics / Male / Hippocampus: metabolism / Signal
Transduction / Brain: metabolism / Mice, Inbred C57BL /
Mice, Transgenic / Mice, Knockout / Cognition: physiology /
Erythropoietin (NLM Chemicals) / Receptors, Erythropoietin
(NLM Chemicals) / Receptor, EphB4 (NLM Chemicals) / Epo
protein, mouse (NLM Chemicals)},
cin = {AG Bansal},
ddc = {610},
cid = {I:(DE-2719)1210013},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354)},
pid = {G:(DE-HGF)POF4-354},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41028570},
doi = {10.1038/s41380-025-03230-7},
url = {https://pub.dzne.de/record/285264},
}