Biology subjects

Manukjan, G.

Publications and source records attributed to Manukjan, G..

3 recordsLinked to original sources

bioRxiv2021

G6b-B regulates an essential step in megakaryocyte maturation

G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entire Mpig6b locus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations in MPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of the Mpig6b locus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange, Mpig6bmut mice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developed Mpig6b null mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.

cell biology↗

bioRxiv2021

How biological cells including platelets and megakaryocytes decide complex problems fast but risky

Short AbstractMathematical decision processes are accurate but sometimes take very long time or simply do not happen. Decisions in biology happen fast and driven by evolution, optimizing survival chances. This results in stochastic decisions with on average good adaptation to the environment but an inherent risk of individual errors e.g. developing cancer during cell regeneration. We calculate and show in platelets and megakaryocytes how cellular decision processes increases risk for errors and inflammation. Short cut solutions adapted from nature improve computer strategies for protein folding and network decision processes. Complex problems are not always solved in foreseeable time, instead the fast solutions in biology speed up errors everywhere including biochemical aging of blood vessels, misfolded proteins, mis-programmed cells, cancer and heart failure. One sentence abstractWe investigate in biological networks how complex decision problems are mastered not by an accurate but unforeseeable long mathematical search but rather pragmatic and fast, with an inherent risk of error, a basis for inflammation and cancer.

bioinformatics↗

bioRxiv2019

Impact of Itga2-Gp6-double collagen receptor deficient mice for bone marrow megakaryocytes and platelets

The two main collagen receptors on platelets, GPVI and integrin 2{beta}1, play an important role for the recognition of exposed collagen at sites of vessel injury, which leads to platelet activation and subsequently stable thrombus formation. Both receptors are already expressed on megakaryocytes, the platelet forming cells within the bone marrow. Megakaryocytes are in permanent contact with collagen filaments in the marrow cavity and at the basal lamina of sinusoids without obvious preactivation. The role of both collagen receptors for megakaryocyte maturation and thrombopoiesis is still poorly understood. To investigate the function of both collagen receptors, we generated mice that are double deficient for Gp6 and Itga2. Flow cytometric analyses revealed that the deficiency of both receptors had no impact on platelet number and the expected lack in GPVI responsiveness. Integrin activation and degranulation ability was comparable to wildtype mice. By immunofluorescence microscopy, we could demonstrate that double-deficient megakaryocytes were overall normally distributed within the bone marrow. We found megakaryocyte count and size to be normal, the localization within the bone marrow, the degree of maturation, as well as their association to sinusoids were also unaltered. However, the contact of megakaryocytes to collagen type I filaments was decreased at sinusoids compared to wildtype mice, while the interaction to type IV collagen was unaffected. Our results imply that GPVI and 2{beta}1 have no influence on the localization of megakaryocytes within the bone marrow, their association to the sinusoids or their maturation. The decreased contact of megakaryocytes to collagen type I might at least partially explain the unaltered platelet phenotype in these mice, since proplatelet formation is mediated by these receptors and their interaction to collagen. It is rather likely that other compensatory signaling pathways and receptors play a role that needs to be elucidated.

cell biology↗