Biology subjects

Bassi, I.

Publications and source records attributed to Bassi, I..

4 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↗

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↗