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bioRxiv · 10.64898/2026.03.20.713161

Evolutionary rewiring of the DNM2 proline-rich domain drives lineage-specific constraints in erythropoiesis

Arbogast, T.·Kirstetter, P.·Kretz, C.·Masson, C.·Chan, S.·Kastner, P.·Eckly, A.·Laporte, J. F.
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Abstract

Dynamin-2 (DNM2) is a ubiquitously expressed GTPase essential for membrane trafficking, yet how its evolution shapes tissue-specific functions remains unclear. Here, we generated a humanized mouse model in which murine Dnm2 is fully replaced by human DNM2. Human DNM2 rescues the embryonic lethality of Dnm2 deletion but cannot sustain postnatal hematopoiesis, leading to fatal hemolytic anemia, erythroblast maturation arrest, reticulocytosis, and macrothrombocytosis. The defect emerges selectively during postnatal bone marrow erythropoiesis and is associated with impaired transferrin receptor turnover, despite normal fetal liver hematopoiesis. Comparative proteomics reveals extensive species-specific rewiring of the DNM2 proline-rich domain (PRD) interactome, with GRB2 as the sole conserved partner. Dnm2 haploinsufficiency phenocopies the erythroid defect with reduced severity, indicating a dosage-sensitive loss-of-function mechanism. These findings identify PRDs as rapidly evolving context-dependent adaptors that tune ubiquitous proteins to tissue-specific demands, and highlight regulatory domains compatibility as a key consideration for humanized models and gene-replacement strategies.

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Arbogast, T., Kirstetter, P., Kretz, C., Masson, C., Chan, S., Kastner, P., Eckly, A., Laporte, J. F.. 2026-03-23. Evolutionary rewiring of the DNM2 proline-rich domain drives lineage-specific constraints in erythropoiesis. https://doi.org/10.64898/2026.03.20.713161

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