Biology subjects

Lele, T.

Publications and source records attributed to Lele, T..

4 recordsLinked to original sources

bioRxiv2025

The nucleus forms a dynamic contact with the plasma membrane to maintain the glandular epithelial architecture

The maintenance of epithelial architecture relies on precise mechanical and biochemical cues. Recent studies reveal an unexpected role for the nucleus in maintaining epithelial architecture, but how the nucleus is physically and molecularly integrated into epithelia remains unclear. Here, we identify a dynamic basal actin spot that links the nucleus to plasma membrane {beta}1-integrin through the linker of nucleoskeleton and cytoskeleton (LINC) in 3D breast acini. Depletion of LINC complex nesprin-2G, SUNs or FHOD1 disrupts nuclear positioning and inhibits lumen formation. Activation of a nesprin-2 degron causes acute loss of the basal actin spot and collapse of acini. Active Src and {beta}1-integrin accumulate in the basal actin spot and Src activity is required to prevent collapse of acinar structure. These findings reveal an unexpected mode of nuclear-plasma membrane contact that we propose homeostatically regulates intracellular contractility through a Src signaling pathway to maintain global epithelial architecture.

cell biology↗

bioRxiv2022

A predictive unifying explanation for nuclear shapes based on a simple geometric principle

Nuclei have characteristic shapes dependent on cell type, which are critical for proper cell function, and nuclei lose their distinct shapes in multiple diseases including cancer, laminopathies, and progeria. Nuclear shapes result from deformations of the sub-nuclear components--nuclear lamina and chromatin. How these structures respond to cytoskeletal forces to form the nuclear shape remains unresolved. Although the mechanisms regulating nuclear shape in human tissues are not fully understood, it is known that different nuclear shapes arise from cumulative nuclear deformations post-mitosis, ranging from the rounded morphologies that develop immediately after mitosis to the various nuclear shapes that roughly correspond to cell shape (e.g., elongated nuclei in elongated cells, flat nuclei in flat cells). Here we establish a simple geometric principle of nuclear shaping: the excess surface area of the nucleus (relative to that of a sphere of the same volume) permits a wide range highly deformed nuclear shapes under the constraints of constant surface area and constant volume, and, when the lamina is smooth (tensed), the nuclear shape can be predicted entirely from these geometric constraints alone for a given cell shape. This principle explains why flattened nuclear shapes in fully spread cells are insensitive to the magnitude of the cytoskeletal forces. We demonstrate this principle by predicting limiting nuclear shapes (i.e. with smooth lamina) in various cell geometries, including isolated on a flat surface, on patterned rectangles and lines, within a monolayer, isolated in a well, or when the nucleus is impinging against a slender obstacle. We also show that the lamina surface tension and nuclear pressure can be estimated from the predicted cell and nuclear shapes when the cell cortical tension is known, and the predictions are consistent with measured forces. These results show that excess lamina surface area is the key determinant of nuclear shapes, and that nuclear shapes can be determined purely by the geometric constraints of constant (but excess) nuclear surface area and nuclear volume, not by the magnitude of the cytoskeletal forces involved.

biophysics↗

bioRxiv2022

Loss of mechanical homeostasis drives epithelial acinar eversion

Epithelial cells lining a gland and cells grown in a soft extracellular matrix polarize with apical proteins exposed to the lumen and basal proteins in contact with the extracellular matrix. Alterations to polarity, including an apical-out polarity, occur in human cancers. While some aberrant polarity states may result from altered protein trafficking, recent observations of an extraordinary tissue-level inside-out unfolding suggest an alternate pathway for altered polarity. Because mechanical alterations are common in human cancer including an upregulation of RhoA mediated actomyosin tension in acinar epithelia, we explored whether perturbing mechanical homeostasis could cause apical-out eversion. Acinar eversion was robustly induced by direct activation of RhoA in normal and tumor epithelial acini, or indirect activation of RhoA through blockage of {beta}1 integrins, disruption of the LINC complex, oncogenic Ras activation, or Rac1 inhibition. Furthermore, laser ablation of a portion of the untreated acinus was sufficient to induce eversion. Analyses of acini revealed high curvature and low phosphorylated myosin in the apical cell surfaces relative to the basal surfaces. A vertex-based mathematical model which balances tension at cell-cell interfaces revealed a five-fold greater basal cell surface tension relative to the apical cell surface tension. The model suggests that the difference in surface energy between the apical and basal surfaces is the driving force for acinar eversion. Our findings raise the possibility that a loss of mechanical homeostasis may cause apical-out polarity states in human cancers.

biophysics↗

bioRxiv2020

Anisotropic random walks reveal chemotaxis signaling output in run-reversing bacteria

The bias for a particular direction of rotation of the flagellar motor is a sensitive readout of chemotaxis signaling, which mediates bacterial migration towards favorable chemical environments. The rotational bias has not been characterized in Helicobacter pylori, which limits our understanding of the signaling dynamics. Here, we determined that H. pylori swim faster (slower) whenever their flagella rotate counterclockwise (clockwise) by analyzing their hydrodynamic interactions with bounding surfaces. The anisotropy in swimming speeds helped quantify the fraction of the time that the cells swam slower to report the first measurements of the bias. A stochastic model of run-reversals indicated that the anisotropy promotes faster spread compared to isotropic swimmers. The approach further revealed that the diffuse spread of H. pylori is likely limited at the physiological temperature due to increased reversal frequencies. Thus, anisotropic run-reversals make it feasible to study signal-response relations in the chemotaxis network in non-model bacterial species. Impact StatementAnisotropy in run and reversal swimming speeds promotes the spread of H. pylori and reveals temperature-dependent behavior of the flagellar switch.

biophysics↗