Biology subjects

Khalaily, L.

Publications and source records attributed to Khalaily, L..

3 recordsLinked to original sources

bioRxiv2025

Multimodal profiling reveals a Notch-responsive regenerative subpopulation of cochlear supporting cells

Regeneration enables organisms to repair damaged tissues, yet this capacity is strikingly limited in the cochlear sensory epithelium, essential for sound detection. A major cause of hearing loss arises from the irreversible loss of sensory hair cells (HCs) in the cochlea. While supporting cells (SCs) have a latent ability to transdifferentiate into HCs, this regenerative potential is rapidly lost after development. Using live imaging and single-cell multi-omics of cochlear explants, we uncovered the cellular and molecular heterogeneity underlying the limited regenerative capacity of the neonatal mouse cochlea. Notch repression broadly silenced key SC genes, yet only a rare subpopulation of Deiters cells (DC), termed transdifferentiating DCs (tDCs), initiated the transdifferentiation into HC fate. These cells underwent coordinated transcriptional and enhancer remodeling, linking epigenetic priming with morphological plasticity, while other SCs remained refractory despite robust Notch targets downregulation. Our study provides a molecular definition of an early induced transitional DC to HC state, revealing Notch inhibition as a selective trigger that unmasks rare regenerative competence.

developmental biology↗

bioRxiv2020

The tolerance to hypoxia is defined by a time-sensitive response of the gene regulatory network in sea urchin embryos

Deoxygenation, the reduction of oxygen level in the oceans induced by global warming and anthropogenic disturbances, is a major threat to marine life. This change in oxygen level could be especially harmful to marine embryos that utilize endogenous hypoxia and redox gradients as morphogens during normal development. Here we show that the tolerance to hypoxic conditions changes between different developmental stages of the sea urchin embryo, due to the structure of the gene regulatory networks (GRNs). We demonstrate that during normal development, bone morphogenetic protein (BMP) pathway restricts the activity of the vascular endothelial growth factor (VEGF) pathway to two lateral domains and by that controls proper skeletal patterning. Hypoxia applied during early development strongly perturbs the activity of Nodal and BMP pathways that affect VEGF pathway, dorsal-ventral (DV) and skeletogenic patterning. These pathways are largely unaffected by hypoxia applied after DV axis formation. We propose that the use of redox and hypoxia as morphogens makes the sea urchin embryo highly sensitive to environmental hypoxia during early development, but the GRN structure provides higher tolerance to hypoxia at later stages. Summary statementThe use of hypoxia and redox gradients as morphogens makes sea urchin early development sensitive to environmental hypoxia. This sensitivity decreases later, due to the structure of the gene regulatory network.

developmental biology↗

bioRxiv2019

Possible co-option of a VEGF-driven tubulogenesis program for biomineralization in echinoderms

Biomineralization is the process in which living organisms use minerals to form hard structures that protect and support them. Biomineralization is believed to have evolved rapidly and independently in different phyla utilizing existing components used for other purposes. The mechanistic understanding of the regulatory networks that drive biomineralization and their evolution is far from clear. The sea urchin skeletogenesis is an excellent model system for studying both gene regulation and mineral uptake and deposition. The sea urchin calcite spicules are formed within a tubular cavity generated by the skeletogenic cells under the control the vascular endothelial growth factor (VEGF) signaling. The VEGF pathway controls tubulogenesis and vascularization across metazoans while its regulation of biomineralization was only observed in echinoderms. Despite the critical role of VEGF signaling in sea urchin spiculogenesis, the downstream program it activates was largely unknown. Here we study the cellular and molecular machinery activated by the VEGF pathway during sea urchin spiculogenesis and reveal multiple parallels to the regulation of tubulogenesis during vertebrate vascularization. Human VEGF rescues sea urchin VEGF knock-down; VEGF-dependent vesicle deposition plays a significant role in both systems and sea urchin VEGF signaling activates hundreds of genes including biomineralization and vascularization genes. Five upstream transcription factors and three signaling genes active in spiculogenesis are homologous to vertebrate factors that regulate vascularization. Overall, our findings suggest that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program, broadly adapted for vascularization and specifically co-opted for biomineralization in the echinoderm phylum. Significance statementThe sea urchin calcite spicules and vertebrate blood vessels are quite distinct in their function, yet both have a tubular structure and are controlled by the vascular endothelial growth factor (VEGF) pathway. Here we study the downstream program by which VEGF pathway drives sea urchin spiculogenesis and find remarkable similarities to the control of vertebrate vascularization. The similarities are observed both in the upstream gene regulatory network, in the downstream effector genes and the cellular processes that VEGF signaling controls at the site of the calcite spicule formation. We speculate that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program that was co-opted for biomineralization in the echinoderm phylum.

evolutionary biology↗