Absence of GPIbalpha is responsible for aberrant membrane development during megakaryocyte maturation: ultrastructural study using a transgenic model
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Christel Poujol1, Jerry Ware, Bernhard Nieswandt
1UMR 5533 CNRS, Laboratoire d'Hématologie, Hôpital Cardiologique, Avenue de Magellan, 33604 Pessac, France.
Objective:
The glycoprotein Ib/IX/V complex (GPIb-IX-V) mediates platelet attachment to von Willebrand factor in exposed subendothelium. Molecular defects in the genes for GPIbalpha, GPIbbeta, and GPIX give rise to the Bernard-Soulier syndrome, in which thrombocytopenia and giant platelets suggest that this receptor also is involved in platelet production. To study how giant platelets are produced in vivo, we used a model of GPIbalpha-deficient mice (GPIbalpha(null)) and mice rescued with the human GPIbalpha transgene (GPIbalpha(null;hTg)).
Materials And Methods:
Using electron microscopy and immunogold labeling, we examined megakaryocytopoiesis in the bone marrow of these mice and developed a method to quantify the membranes of megakaryocytes (MK) and proplatelets by computer analysis.
Results:
Abnormal membrane development in the perinuclear zone was found in immature MK of GPIbalpha(null) mice. This led to a poorly developed demarcation membrane system and other ultrastructural changes. As a result, well-organized platelet territories were rarely seen within the cytoplasm of mature MK. Membrane quantification confirmed that MK of GPIbalpha(null) mice had a reduced internal membrane pool. Whereas these MK normally crossed the endothelial barrier, their migration was accompanied by the production of unusually large MK fragments or proplatelets in the vascular sinus with an approximately 50% decrease in internal membrane content compared to wild-type. In the rescued GPIbalpha(null;hTg) model, GPIbalpha was normally localized in MK, and there was a total correction of the ultrastructural defects.
Conclusions:
GPIbalpha is essential for membrane development and distribution in maturing MK. Its absence leads to abnormal partitioning of the membrane systems and abnormal proplatelet production.
Insights
Glycoprotein Ib-alpha (GPIbα) is crucial for normal platelet production. Its absence causes abnormal membrane development in megakaryocytes, leading to giant platelets and impaired proplatelet formation.
Area of Science:
- Hematology
- Cell Biology
- Molecular Biology
Background:
- The glycoprotein Ib/IX/V complex (GPIb-IX-V) facilitates platelet adhesion to von Willebrand factor.
- Defects in GPIb-IX-V genes cause Bernard-Soulier syndrome, characterized by thrombocytopenia and giant platelets, suggesting a role in platelet production.
Purpose of the Study:
- To investigate the in vivo mechanisms of giant platelet production.
- To elucidate the role of GPIbα in megakaryocyte membrane development and proplatelet formation.
Main Methods:
- Utilized GPIbα-deficient mice and rescued transgenic models.
- Employed electron microscopy and immunogold labeling to examine megakaryocytopoiesis.
- Developed a computer-assisted method for quantifying megakaryocyte and proplatelet membranes.
Main Results:
- GPIbα-deficient megakaryocytes exhibited abnormal perinuclear membrane development and a reduced internal membrane pool.
- Impaired demarcation membrane system formation led to poorly organized platelet territories within mature megakaryocytes.
- Megakaryocytes in GPIbα-deficient mice produced larger, membrane-deficient proplatelet fragments, with a ~50% reduction in internal membrane content.
Conclusions:
- GPIbα is essential for proper membrane development and distribution during megakaryocyte maturation.
- Absence of GPIbα results in aberrant membrane partitioning and abnormal proplatelet production, contributing to giant platelet formation.
