Laboratory for Cellular Architecture| Red Blood Cell Research | |
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One focus of our research is the role of Tmod in the organization and function of the spectrin-actin network of the RBC membrane skeleton. The spectrin-actin network is arranged as a quasi-hexagonal network in which the strands are long spectrin tetramers and the vertices are short actin filaments, capped by Tmod1 and with short a and gTMs along their length. A priori, polymerization and stability of the actin filament linkers is expected, but not proven, to be critical for the network’s long-range connectivity and functions. To better study Tmod1 function in RBCs, we rescued the embryonic lethality by expressing a Tmod1 transgene in the heart under the control of the a-myosin heavy chain promoter, Tg(aMHC‑Tmod1), obtaining viable Tmod1‑/‑Tg(aMHC-Tmod1) adult mice with no Tmod1 in any tissues except their heart. Our studies show that absence of Tmod1 leads to a mild compensated hemolytic anemia, indicative of RBC membrane instability and reduced survival in the circulation. However, analysis of the membrane skeleton revealed increased Tmod3, with no major changes in actin, TM or other components, likely accounting for the mild RBC phenotype. Generation of a double knockout for Tmod1 and Tmod3 is in progress. |
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