Biology subjects

Jung, H. M.

Publications and source records attributed to Jung, H. M..

4 recordsLinked to original sources

bioRxiv2025

Shoc2 Deficiency Disrupts Lymphangiogenesis through mTOR-Mediated Mitochondrial Dysfunction

An interplay of growth factors and signaling pathways governs the development and maintenance of the lymphatic vasculature, ensuring proper fluid homeostasis and immune function. Disruption of these regulatory mechanisms can lead to congenital lymphatic disorders and contribute to various pathological conditions. However, the mechanisms underlying the molecular regulation of these processes remain elusive. Here we reveal a critical and previously unappreciated role for the signaling scaffold protein Shoc2 in lymphangiogenesis. We demonstrate that loss of Shoc2 leads to nearly a complete loss of lymphatic vasculature in vivo and senescence of lymphatic endothelial cells in vitro. Mechanistically, Shoc2 is required for balancing signaling through the ERK1/2 pathway, and its loss results in increased mTORC1 signaling. This dysregulation impairs mitochondrial respiration and triggers an IRF/IFN-II response, ultimately leading to cellular senescence. Strikingly, expression of the Noonan Syndrome with Loose anagen Hair (NSLH)-causing Shoc2 variant S2G phenocopies the effects of Shoc2 loss. Together, these studies establish the critical role of Shoc2 in lymphangiogenesis and uncover a novel mechanistic link between Shoc2 signaling, mitochondrial function, innate immune response, and lymphatic development, with significant implications for Ras-pathway-related congenital disorders.

developmental biology↗

bioRxiv2024

Tissue Regeneration Requires Edema Fluid Clearance by Compensatory Lymphangiogenesis in Zebrafish

Lymphangiogenesis is essential for tissue regeneration and edema clearance, and delayed or failed lymphangiogenesis is a critical cause of impaired healing. However, elucidating the dynamic changes in lymphangiogenesis during tissue regeneration in animal models in real-time has been challenging; thus, the mechanisms of compensatory lymphatic activation for edema clearance remain unclear. To address this, zebrafish were subjected to osmotic stress using a hypertonic solution (375 mOsm/L) and hypotonic solution (37.5 mOsm/L) to induce tissue damage followed by edema formation. Intravital imaging of Tg(mrc1a:egfp; kdrl:mcherry) larvae unveiled substantial lymphatic vessel remodeling during tissue regeneration. The increase of lymphatic endothelial progenitor cells accompanied by sustained expansion and remodeling of primary lymphatics during recovery suggested active lymphangiogenesis during tissue repair. We developed a novel method using translating ribosome affinity purification to scrutinize the translatome of lymphatic endothelial cells in vivo. This analysis revealed the upregulation of key pro-lymphangiogenic genes, notably vegfr2 and vegfr3, during tissue regeneration. Pharmacological inhibition of these Vegfr2/Vegfr3 prevented compensatory lymphangiogenesis and impaired healing. Our findings provide a new model of in vivo live imaging of regenerative lymphangiogenesis, presenting a novel approach to investigating lymphatic activation during tissue regeneration.

developmental biology↗

bioRxiv2020

Live Imaging of Intracranial Lymphatics in the Zebrafish

RationaleThe recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish have made this an essential model organism for studying lymphatic development, the existence of meningeal lymphatics has not yet been reported in this species. ObjectiveExamine the intracranial space of larval, juvenile, and adult zebrafish to determine whether and where intracranial lymphatic vessels are present. Methods and ResultsUsing high-resolution optical imaging of the meninges in living animals, we show that zebrafish possess a meningeal lymphatic network comparable to that found in mammals. We confirm that this network is separate from the blood vascular network and that it drains interstitial fluid from the brain. We document the developmental origins and growth of these vessels into a distinct network separated from the external lymphatics. Finally we show that these vessels contain immune cells and perform live imaging of immune cell trafficking and transmigration in meningeal lymphatics. ConclusionsThis discovery establishes the zebrafish as a important new model for experimental analysis of meningeal lymphatic development, and opens up new avenues for probing meningeal lymphatic function in health and disease.

developmental biology↗

bioRxiv2019

MicroRNA-mediated control of developmental lymphangiogenesis

The post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved miRNA dramatically enriched in lymphatic vs. blood endothelial cells, and we demonstrate that this miRNA plays a critical role during lymphatic development. Suppressing miR-204 leads to loss of lymphatic vessel formation, while overproducing miR-204 in lymphatic vessels accelerates lymphatic vessel formation, suggesting a positive role during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key conserved target for post-transcriptional regulation by miR-204 during lymphangiogenesis. While miR-204 suppression leads to loss of lymphatics, knocking down its target NFATC1 leads to lymphatic hyperplasia, and the loss of lymphatics in miR-204-deficient animals can be rescued by NFATC1 knockdown. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

developmental biology↗