Biology subjects

Moshe, N.

Publications and source records attributed to Moshe, N..

3 recordsLinked to original sources

bioRxiv2021

Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells

The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet, the functional relevance of deriving a specific cell type from ontologically distinct progenitors, remains an open question. In the case of the vascular system, blood and lymphatic vessels are composed of endothelial cells (ECs) that differentiate and diversify to cater the different physiological demands of each organ. While lymphatic vessels have been shown to originate from multiple cell sources, lymphatic ECs (LECs) themselves seem to have a unipotent cell fate. In this work we uncover a novel mechanism of blood vessel formation through transdifferentiation of LECs. Using advanced long-term reiterative imaging and lineage-tracing of ECs in zebrafish, from embryonic development through adulthood, we reveal a hitherto unknown process of LEC-to-BEC transdifferentiation, underlying vascularization of the anal fin (AF). Moreover, we demonstrate distinct functional implications for deriving AF vessels from either LECs or BECs, uncovering for the first time a clear link between cell ontogeny and functionality. Molecularly, we identify Sox17 as a negative regulator of lymphatic fate specification, whose specific expression in AF LECs suppresses its lymphatic cell fate. Finally, we show that akin to the developmental process, during adult AF regeneration the vasculature is re-derived from lymphatics, demonstrating that LECs in the mature fish retain both potency and plasticity for generating specialized blood vessels. Overall, our work highlights a novel mechanism of blood vessel formation through LEC trans-differentiation, and provides the first in vivo evidence for a link between cell ontogeny and functionality in ECs.

developmental biology↗

bioRxiv2021

Novel zebrafish mutants reveal new roles for Apolipoprotein B during embryonic development and pathological conditions

Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs and LDLs and is essential for their assembly. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia. Conversely, high levels of APOB in plasma are associated with increased risk for coronary heart disease and atherosclerosis. The involvement of APOB in lipid metabolism and atherogenesis prompted the generation of several mutant mice. However, as APOB is required for supplying nutrients to the developing embryo, ApoB null mice are embryonic lethal, thereby precluding the study of the roles of this protein during development. Here, we established novel zebrafish mutants for two apoB genes: apoBa and apoBb.1. Double-mutant embryos display clear hallmarks of human hypolipidemia-related diseases, including intestinal defects and fatty liver, as well as profound vascular defects. We further use these models to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, our novel zebrafish models uncover new functions of ApoB in organ development and morphogenesis and shed new light on the mechanisms underlying hypolipidemia-related diseases.

developmental biology↗

bioRxiv2020

VEGFC induced cell cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells

The emergence and growth of new vessels requires a tight synchronization between proliferation, differentiation and sprouting, traditionally thought to be controlled by mitogenic signals, especially of the VEGF family. However, how these cues are differentially transduced, by sometimes even neighboring endothelial cells (ECs), remains unclear. Here we identify cell-cycle progression as a new regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell-cycle stages, we show that venous and lymphatic precursors sprout from the Cardinal Vein (CV) exclusively in G0/G1, and reveal that cell-cycle arrest is induced in these ECs by p53 and the CDK-inhibitors p27 and p21. Moreover, we demonstrate that in vivo, chemical and genetic cell-cycle inhibition, results in massive vascular growth. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as direct inducer of cell-cycle arrest in angiogenic ECs and characterize the cascade of events governing venous vs. lymphatic segregation and sprouting. Overall, our results uncover an unexpected mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell-cycle inhibitors in pathological angiogenesis and lymphangiogenesis.

developmental biology↗