A new mouse model of thrombopoietin deficiency arising from a spontaneous single base pair mutation
Year: 2025
Type: article
Abstract: Thrombopoietin (TPO) is the principal regulator of bone marrow platelet production and plays an important role in maintaining hematopoietic stem and progenitor cells. Predominantly produced in the liver, circulating TPO levels are primarily modulated through receptor-mediated clearance of TPO by target cells such as platelets. However, there is an additional component of TPO regulation at the transcriptional level, which may be affected in the setting of platelet-associated diseases. Current TPO knockout mouse models partially limit the study of transcriptional regulation because of disruption of the TPO genomic locus. Here, we describe a novel mouse model of TPO deficiency arising from a spontaneous mutation in a single base pair within exon 5 of the TPO gene. The resulting amino acid change (leucine to histidine at position 121) predicts a dramatic alteration in protein structure, ultimately resulting in a ~ 95% decrease of circulating TPO. The hematological phenotype of this new C57Bl/6(IMPC)J-TPOL121H strain mimics that of other mouse models of TPO deficiency, but the genomic locus remains intact and therefore preserves normal TPO transcriptional regulation. We characterize the hematological phenotype of this new strain and discuss its applications as a model of transcriptional TPO regulation and clinical thrombocytopenia. Our findings highlight the theoretical possibility that TPO protein destabilizing mutations may explain rare cases of patient thrombocytopenia. Thrombopoietin is a protein and a hormone that is predominantly produced in the liver. Thrombopoietin helps the body to produce different types of blood cells, especially platelets. Platelets are important for the formation of blood clots in the setting of bleeding. Patients with low levels of thrombopoietin can have spontaneous and excessive bleeding, which can be severe and even life-threatening. Therefore, it is important to understand how the body controls thrombopoietin levels. We discovered a new laboratory mouse that has a very small change in the thrombopoietin gene, but this results in a very big decrease in how much hormone is generated by the liver. These mice also have low platelet levels like many human patients. We hope that this new mouse model can be used to understand how thrombopoietin is regulated in both mice and in humans. Ultimately, we hope that this type of research benefits patients with low platelet counts and other blood disorders.
Source: Figshare
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7117585046