Abstract
The biconcave disk shape of the mammalian red blood cell (RBC) is unique to the RBC and is vital for its circulatory function. Due to the absence of a transcellular cytoskeleton, RBC shape is determined by the membrane skeleton, a network of actin filaments cross-linked by spectrin and attached to membrane proteins. While the physical properties of a uniformly distributed actin network interacting with the lipid bilayer membrane have been assumed to control RBC shape, recent experiments reveal that RBC biconcave shape also depends on the contractile activity of nonmuscle myosin IIA (NMIIA) motor proteins. Here, we use the classical Helfrich-Canham model for the RBC membrane to test the role of heterogeneous force distributions along the membrane and mimic the contractile activity of sparsely distributed NMIIA filaments. By incorporating this additional contribution to the Helfrich-Canham energy, we find that the RBC biconcave shape depends on the ratio of forces per unit volume in the dimple and rim regions of the RBC. Experimental measurements of NMIIA densities at the dimple and rim validate our prediction that (a) membrane forces must be non-uniform along the RBC membrane and (b) the force density must be larger in the dimple than the rim to produce the observed membrane curvatures. Furthermore, we predict that RBC membrane tension and the orientation of the applied forces play important roles in regulating this force-shape landscape. Our findings of heterogeneous force distributions on the plasma membrane for RBC shape maintenance may also have implications for shape maintenance in different cell types.
Highlights
Cell shape and function are intricately coupled; cells must maintain specific shapes to migrate, divide normally, form tissues and organs during development, and support their physiological functions [1,2]
The spectrin-actin network of the membrane skeleton plays an important role in controlling specialized cell membrane morphology
In the paradigmatic red blood cell (RBC), where actin filaments are present exclusively in the membrane skeleton, recent experiments reveal that nonmuscle myosin IIA (NMIIA) motor contractility maintains the red blood cells (RBCs)
Summary
Cell shape and function are intricately coupled; cells must maintain specific shapes to migrate, divide normally, form tissues and organs during development, and support their physiological functions [1,2]. Networks of actin filaments (F-actin) and the F-actin-activated motor protein non-muscle myosin II (NMII) specify cell shape by exerting forces on the plasma membrane to control membrane tension and curvature [5,6,7,8] These actomyosin networks determine cell shapes and interactions during tissue morphogenesis in development [6,9,10,11,12,13] and their dysregulation has been implicated in cancer, [14,15,16], hearing disorders [17], podocyte filtration in the kidney [17,18], and neurodegeneration [19], among other physical issues. The RBC membrane is supported by the membrane skeleton, a two-dimensional network of short F-actins interconnected by long, flexible spectrin molecules [26,27], which bind to transmembrane proteins to maintain membrane tension, curvature, and mechanical properties of the RBC [23,24,26,28,29]
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