TY  - JOUR
AU  - Butt, Umer Javed
AU  - Çakır, Umut
AU  - Wildenburg, Anne-Fleur
AU  - Curto, Yasmina
AU  - Ye, Liu
AU  - Bansal, Vikas
AU  - Boretius, Susann
AU  - Nave, Klaus-Armin
AU  - Singh, Manvendra
AU  - Ehrenreich, Hannelore
TI  - Forebrain-specific loss of erythropoietin provokes compensatory upregulation of different EPO receptors.
JO  - Molecular psychiatry
VL  - 31
IS  - 3
SN  - 1359-4184
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00206
SP  - 1241 - 1252
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Erythropoietin: metabolism
KW  - Erythropoietin: genetics
KW  - Prosencephalon: metabolism
KW  - Receptors, Erythropoietin: metabolism
KW  - Receptors, Erythropoietin: genetics
KW  - Mice
KW  - Memory, Short-Term: physiology
KW  - Up-Regulation
KW  - Receptor, EphB4: metabolism
KW  - Receptor, EphB4: genetics
KW  - Male
KW  - Hippocampus: metabolism
KW  - Signal Transduction
KW  - Brain: metabolism
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Mice, Knockout
KW  - Cognition: physiology
KW  - Erythropoietin (NLM Chemicals)
KW  - Receptors, Erythropoietin (NLM Chemicals)
KW  - Receptor, EphB4 (NLM Chemicals)
KW  - Epo protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41028570
DO  - DOI:10.1038/s41380-025-03230-7
UR  - https://pub.dzne.de/record/285264
ER  -