Biology subjects

Moshe, N.

Publications and source records attributed to Moshe, N..

7 recordsLinked to original sources

bioRxiv2026

Conserved and divergent programs govern cerebellar output neuron development in zebrafish

Cerebellar output neurons transmit the results of cerebellar computation to other brain regions. In most vertebrates, cerebellar output neurons form discrete nuclei, whereas in teleosts they are represented by eurydendroid cells, which differ markedly in morphology and anatomical organization. How these divergent output systems are developmentally related remains unclear. Here, we show that zebrafish eurydendroid cells arise from atoh1a-expressing progenitors, including a population expressing olig2, revealing a developmental origin shared with cerebellar output neurons in other vertebrates. atoh1a is required for eurydendroid cell differentiation and regulates lhx9 and lhx2b, which promote robo1 and robo3 expression and proper axon guidance. Our findings also suggest a role for Reelin signaling in eurydendroid cell positioning. Together, these findings reveal conserved developmental features shared by cerebellar output neurons across vertebrates, as well as mechanisms underlying the distinct anatomical organization of teleost eurydendroid cells.

developmental biology↗

bioRxiv2025

A Conserved Venous Remodeling Program Governs Inferior Vena Cava Formation in Zebrafish

The Inferior Vena Cava (IVC), the largest venous conduit in mammals, forms through complex remodeling of the embryonic cardinal veins (CVs), a process prone to congenital anomalies, with significant clinical implications. However, the mechanisms underlying IVC formation remain unclear. Here, we identify a conserved IVC in zebrafish that emerges during metamorphosis through remodeling of the embryonic CVs, mirroring the mammalian process. Using in vivo imaging and clonal lineage tracing, we identify the cellular origins and molecular mechanisms controlling IVC formation and demonstrate that the transition from CV to IVC represents a shift from a multifunctional embryonic vein to a specialized adult conduit adapted for high-volume blood return. Overall, our findings illuminate conserved mechanisms of venous remodeling and establish a foundation for investigating congenital venous anomalies.

developmental biology↗

bioRxiv2024

A high-throughput zebrafish screen identifies novel candidate treatments for Kaposiform Lymphangiomatosis (KLA)

Kaposiform Lymphangiomatosis (KLA) is a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by driving conditional expression of the human NRAS mutation in venous and lymphatic ECs. We find that mutant embryos recapitulated clinical features of KLA, including pericardial edema and a dilated thoracic duct, and that the phenotypes were reverted by Trametinib, a MEK inhibitor used for KLA treatment. We further leverage this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes and identify Cabozantinib, an FDA-approved tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as leading hits. Finally, we test these drugs in cultured cells derived from KLA patient and demonstrate their ability to normalize LEC sprouting and block NRAS downstream pathways, underscoring the potential of GSK690693 and Cabozantinib as potential KLA treatments. Overall, our novel zebrafish model provides a valuable tool for research into the etiology of KLA and for identifying new therapeutic avenues.

developmental biology↗

bioRxiv2023

Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised Blood-Brain Barrier integrity

The neurovascular unit (NVU) is a complex structure comprising neurons, glia, and pericytes that interact with specialized endothelial cells to maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. Alterations to NVU formation and function can lead to serious forms of cerebrovascular disease, including cerebral small vessel diseases (CSVDs), a range of pathological changes of cerebral capillaries within the white matter contributing to BBB dysfunction and demyelination. Despite the growing recognition of the pivotal roles played by neuro-vascular and glia-vascular interfaces in NVU formation and functioning, CSVD research has mainly focused on characterizing pericyte and EC dysfunction, leaving our understanding of the contribution of non-vascular cells of the brain parenchyma limited. Here, we use a novel zebrafish mutant to delve into the intricate interplay among NVU components and demonstrate how the compromised specification of a progenitor cell population sets off a cascade of events, ultimately leading to severe cerebrovascular abnormalities. The mutation affects Scavenger Receptor B2 (scarb2)/Lysosomal Membrane Protein 2 (limp2), a highly conserved protein residing in the membrane of late endosomes and lysosomes. We find Scarb2 to be predominantly expressed in Radial Glia Cells (RGCs), a multipotent cell giving rise to neurons and glia in both zebrafish and mammals. Through live imaging and genetic manipulations, we identify impaired Notch3 signaling in RGCs and their glial progeny as the primary consequence of Scarb2a depletion and show that this disruption causes excessive neurogenesis at the expense of glial cell differentiation. We further pinpoint compromised acidification of the endolysosomal compartment in mutant cells as the underlying cause of disrupted Notch3 processing, linking for the first time Notch3 defects in non-vascular cells of the brain parenchyma to CSVD phenotypes. Given the evolutionary conservation of SCARB2 expression and the remarkable recapitulation of CSVD phenotypes, scarb2 mutants provide a promising framework for investigating the mechanisms governing Notch3 processing in non-vascular cells and their involvement in the onset of CSVD.

developmental biology↗

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↗