Details

Autor(en) / Beteiligte

• Taneja, Nilay

Titel

Role of Mechanical Forces in Mitosis and Heart Muscle

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2020

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The molecular motor myosin-II (MII) generates mechanical tension on the actin cytoskeleton to drive cell shape changes during cell division, cell migration and tissue morphogenesis. How these actomyosin networks generate force at the molecular scale, how this force generation is controlled in space and time, and how these molecular events translate to cellular behavior remain open questions. These questions were investigated using cell division and sarcomere formation as conceptual paradigms. A specific paralog of MII, MIIA, was found to generate surface tension during cell division, and was required for faster contractile ring constriction, as well as powering the formation and retraction of membrane blebs, specialized protrusions that release excess pressure in dividing cells. MIIB, on the other hand, maintained network integrity during contractions. These functions were regulated both by composition of MIIA/B heterofilaments and motor turnover. Disturbing the composition of MIIA/B heterofilaments resulted in division failure and chromosome mis-segregation. Actomyosin networks also help cells sense and transduce cues from the extracellular matrix (ECM), mediated by protein assemblies called focal adhesions. Dividing cells were found to contain actively regulated focal adhesions, which shaped the cleavage furrow by generating resistive forces against contractile ring constriction. This force-balance also regulated spindle orientation and inheritance of the mother centrosome. A similar force balance between adhesion and contraction was found during sarcomere formation in cardiac myocytes. Cardiac sarcomeres arise from non-muscle like stress fibers. Focal adhesions were found to serve as load-bearing sites during this process and were required for stress fibers to increase their force generating capacity as they accumulated muscle-specific machinery. Coupling to focal adhesions also altered the material properties of myofibrils, with increased adhesion resulting in increased myofibril viscosity. Taken together, these results have revealed new insights and common principles underlying contractile force generation within actomyosin networks, and the nature of resistive forces generated by cell-ECM adhesion, in the context of two fundamental cellular processes, cell division and myofibril assembly.