Biology subjects

Odell, J.

Publications and source records attributed to Odell, J..

4 recordsLinked to original sources

bioRxiv2025

A-type lamins anchor emerin at the inner nuclear membrane via two independent binding sites

Lamins form a dense meshwork at the inner surface of the inner nuclear membrane (INM), where they interact with other nuclear envelope proteins such as emerin. Emerin is an integral membrane protein that is part of the LEM (LAP2/emerin/MAN1) domain family, and mutations in either emerin or lamin A/C can result in Emery-Dreifuss muscular dystrophy (EDMD) and other striated muscle diseases. Emerin is retained at the INM through direct interaction with lamin A/C, and emerins proper subcellular localization is critical for its ability to influence the mechanical properties of the nucleus and participate in various signaling processes. Nonetheless, the requirements for interaction between emerin and lamin A/C at the INM remain incompletely understood. Here, we report that two distinct regions of lamin A/C are each sufficient to properly localize emerin to the INM and prevent emerins lateral diffusion within the INM. In addition to a previously described region of the lamin A/C tail domain able to bind emerin, we identify a novel emerin-interacting domain comprising the linker between the rod and Ig-like fold domains of lamin A/C. We further demonstrate that stably anchoring emerin to the INM requires assembly of A-type lamins into a filamentous network. Collectively, our findings suggest a revised model for emerin retention at the INM, which predicts that two independent lamin A/C domains are required to retain emerin at the nuclear envelope.

cell biology↗

bioRxiv2025

The Deformability of the Mammalian Cell Nucleus is Determined by the Identity of the Lamin Rod Domain

Lamins are nuclear intermediate filament proteins with diverse functions, ranging from organizing chromatin and regulating gene expression to providing structural support to the nucleus. Mammalian cells express two types of lamins, A-type and B-type, which, despite their similar structure and biochemical properties, exhibit distinct differences in expression, interaction partners, and function. One major difference is that A-type lamins have a significantly larger effect on the mechanical properties of the nucleus, which are crucial for protecting the nucleus from cytoskeletal forces, enabling cell migration through confined spaces, and contributing to cellular mechanotransduction. The molecular mechanism underlying this difference has remained unresolved. Here, we applied custom-developed biophysical and proteomic assays to lamin-deficient cell lines engineered to express specific full-length lamin proteins, lamin truncations, or chimeras combining domains from A- and B-type lamins, to systematically determine their contributions to nuclear mechanics. We found that although all expressed lamins contribute to the biophysical properties of the nuclear interior and confer some mechanical stability to the nuclear envelope, which is sufficient to protect the nuclear envelope from small cell-intrinsic forces and ensure proper positioning of nuclear pores, A-type lamins endow cells with a unique ability to resist large forces on the nucleus. Surprisingly, this effect was conferred through the A-type lamin rod domain, rather than the head or tail domains, which diverge more substantially between A- and B-type lamins and play important roles in lamin network formation. Collectively, our work provides an improved understanding of the distinct functions of different lamins in mammalian cells and may also explain why mutations in the A-type lamin rod domain cause more severe muscle defects in mouse models than other mutations.

cell biology↗

bioRxiv2024

Metastatic organotropism in small cell lung cancer

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

cancer biology↗

bioRxiv2024

N-terminal tags impair the ability of Lamin A to provide structural support to the nucleus

Lamins are intermediate filament proteins that contribute to numerous cellular functions, including nuclear morphology and mechanical stability. The N-terminal head domain of lamin is critical for higher order filament assembly and function, yet the effects of commonly used N-terminal tags on lamin function remain largely unexplored. Here, we systematically studied the effect of two differently sized tags on Lamin A (LaA) function in a mammalian cell model engineered to allow for precise control of expression of tagged lamin proteins. Untagged, FLAG-tagged, and GFP-tagged LaA completely rescued nuclear shape defects when expressed at similar levels in lamin A/C-deficient (Lmna-/-) MEFs, and all LaA constructs prevented increased nuclear envelope (NE) ruptures in these cells. N-terminal tags, however, altered the nuclear localization of LaA and impaired the ability of LaA to restore nuclear deformability and to recruit Emerin to the nuclear membrane in Lmna-/- MEFs. Our finding that tags impede some LaA functions but not others may explain the partial loss of function phenotypes when tagged lamins are expressed in model organisms and should caution researchers using tagged lamins to study the nucleus.

cell biology↗