Biology subjects

Martin-Blanco, E.

Publications and source records attributed to Martin-Blanco, E..

9 recordsLinked to original sources

bioRxiv2025

Failure of DNA repair leads to the tumorigenic transformation of a regenerating blastema in Drosophila imaginal discs

We present a Drosophila model demonstrating that repeated cycles of tissue regeneration following localized apoptosis can induce tumorigenesis in the absence of oncogene activation or tumor suppressor loss. Chronic regenerative stress leads to epithelial disorganization, loss of cell polarity, immune cell infiltration, DNA damage, centrosomal defects, and aneuploidy-- classical hallmarks of cancer. A subset of "walking dead" cells resists apoptosis and contributes to tissue overgrowth and heterogeneity. Single-cell transcriptomics identifies a distinct cell population, absent from normal tissue, emerging under both regenerative and tumorigenic conditions and characterized by enrichment in JNK pathway components. The tumorigenic signature specifically features distinctive JNK regulatory elements while excluding chaperone proteins. Notably, inhibition of JNK signaling or modulation of DNA repair suppresses neoplastic transformation. This model reveals how chronic injury and defective regeneration drive cancer initiation, establishing a mechanistic link between wound healing and tumorigenesis, and providing a powerful system to explore early tumor development and therapeutic intervention.

developmental biology↗

bioRxiv2024

'Mitotic' kinesin-5 is a dynamic brake for axonal growth

During neuronal development, neurons undergo significant microtubule reorganization to shape axons and dendrites, establishing the framework for efficient wiring of the nervous system. Previous studies from our laboratory demonstrated the key role of kinesin-1 in driving microtubule-microtubule sliding, which provides the mechanical forces necessary for early axon outgrowth and regeneration in Drosophila melanogaster. In this study, we reveal the critical role of kinesin-5, a mitotic motor, in modulating the development of postmitotic neurons. Kinesin-5, a conserved homotetrameric motor, typically functions in mitosis by sliding antiparallel microtubules apart in the spindle. Here, we demonstrate that the Drosophila kinesin-5 homolog, Klp61F, is expressed in larval brain neurons, with high levels in ventral nerve cord (VNC) neurons. Knockdown of Klp61F using a pan-neuronal driver leads to severe locomotion defects and complete lethality in adult flies, mainly due to the absence of kinesin-5 in VNC motor neurons during early larval development. Klp61F depletion results in significant axon growth defects, both in cultured and in vivo neurons. By imaging individual microtubules, we observe a significant increase in microtubule motility, and excessive penetration of microtubules into the axon growth cone in Klp61F-depleted neurons. Adult lethality and axon growth defects are fully rescued by a chimeric human-Drosophila kinesin-5 motor, which accumulates at the axon tips, suggesting a conserved role of kinesin-5 in neuronal development. Altogether, our findings show that at the growth cone, kinesin-5 acts as a brake on kinesin-1-driven microtubule sliding, preventing premature microtubule entry into the growth cone. This regulatory role of kinesin-5 is essential for precise axon pathfinding during nervous system development.

cell biology↗

bioRxiv2022

FGF signaling promotes precursor spreading for adult adipogenesis in Drosophila

Knowledge of adipogenetic mechanisms is essential to understand and treat conditions affecting organismal metabolism and adipose tissue health. In Drosophila, mature adipose tissue (fat body) exists in larvae and adults. In contrast to the well-known development of the larval fat body from the embryonic mesoderm, adult adipogenesis has remained mysterious. Furthermore, conclusive proof of its physiological significance is lacking. Here, we show that the adult fat body originates from a pool of undifferentiated mesodermal precursors that migrate from the thorax into the abdomen during metamorphosis. Through in vivo imaging, we found that these precursors spread from the ventral midline and cover the inner surface of the abdomen in a process strikingly reminiscent of embryonic mesoderm migration, requiring FGF signaling as well. FGF signaling guides migration dorsally and regulates adhesion to the substrate. After spreading is complete, precursor differentiation involves fat accumulation and cell fusion that produces mature binucleate and tetranucleate adipocytes. Finally, we show that flies where adult adipogenesis is impaired by knock down of FGF receptor Heartless or transcription factor Serpent display ectopic fat accumulation in oenocytes and decreased resistance to starvation. Our results reveal that adult adipogenesis occurs de novo during metamorphosis and demonstrate its crucial physiological role.

developmental biology↗

bioRxiv2021

Condensation of the Drosophila Nerve Cord is Oscillatory and depends on Coordinated Mechanical Interactions

During development, organs must form with precise shapes and sizes. Organ morphology is not always obtained through growth; a classic counterexample is condensation of the nervous system during Drosophila embryogenesis. The mechanics underlying such condensation remain poorly understood. Here, we combine in toto live-imaging, biophysical and genetic perturbations, and atomic force microscopy to characterize the condensation of the Drosophila ventral nerve cord (VNC) during embryonic development at both subcellular and tissue scales. This analysis reveals that condensation is not a unidirectional continuous process, but instead occurs through oscillatory contractions alternating from anterior and posterior ends. The VNC mechanical properties spatially and temporally vary during its condensation, and forces along its longitudinal axis are spatially heterogeneous, with larger ones exerted between neuromeres. We demonstrate that the process of VNC condensation is dependent on the coordinated mechanical activities of neurons and glia. Finally, we show that these outcomes are consistent with a viscoelastic model of condensation, which incorporates time delays due to the different time scales on which the mechanical processes act, and effective frictional interactions. In summary, we have defined the complex and progressive mechanics driving VNC condensation, providing insights into how a highly viscous tissue can autonomously change shape and size.

developmental biology↗

bioRxiv2020

ECM remodeling and spatial cell cycle coordination determine tissue growth kinetics

During development, multicellular organisms undergo stereotypical patterns of tissue growth to yield organs of highly reproducible sizes and shapes. How this process is orchestrated remains unclear. Analysis of the temporal dynamics of tissue growth in the Drosophila abdomen reveals that cell cycle times are spatially correlated and that growth termination occurs through the rapid emergence of a population of arrested cells rather than a gradual slowing down of cell cycle time. Reduction in apical tension associated with tissue crowding has been proposed as a developmental growth termination mechanism. Surprisingly, we find that growth arrest in the abdomen occurs while apical tension increases, showing that in this tissue a reduction in tension does not underlie the mechanism of growth arrest. However, remodeling of the extracellular matrix is necessary for tissue expansion. Thus, changes in the tissue microenvironment, and a rapid exit from proliferation, control the formation of the adult Drosophila abdomen.

developmental biology↗

bioRxiv2017

Contractility, Differential Tension and Membrane Removal direct zebrafish Epiboly Biomechanics

Precise tissue remodeling during development is essential for shaping embryos and for optimal organ function. Epiboly is an early gastrulation event by which the blastoderm expands around the yolk to engulf it. Three different layers are involved, an epithelial layer (the enveloping layer, EVL), the embryo proper, constituted by the deep cells (DCs), and the yolk cell. Although teleost epiboly has been studied for many years, a clear understanding of its mechanics was still missing. Here we present new information on the cellular, molecular and mechanical elements involved in epiboly that, together with some other recent data and upon comparison with previous biomechanical models, lets conclude that the expansion of the epithelia is passive and driven by cortical contraction and membrane removal in the adjacent layer, the External Yolk Syncytial Layer (E-YSL). The isotropic actomyosin contraction of the E-YSL generates an anisotropic stress pattern and a directional net movement as a result of the differences in the deformation response of two opposites adjacent domains (the EVL and the Yolk Cytoplasmic Layer - YCL). Contractility is accompanied by the local formation of membrane folds and the membrane removal by Rab5ab dependent macropinocytosis. The increase in area of the epithelia during the expansion is achieved by cell-shape changes (flattening) responding to spherical geometrical cues. The counterbalance between the geometry of the embryo and forces dissipation is therefore essential for epiboly global coordination.

developmental biology↗

bioRxiv2016

Rab5-mediated Yolk Endocytosis modulates Zebrafish Epiboly Biomechanics and Tissue Movements

Morphogenetic processes demand the coordinated allocation of cells and tissues to their final destination in a spatio-temporal controlled way. Identifying how these morphogenetic movements are directed and implemented is essential for understanding morphogenesis. Topographical and scalar differences in adhesion and contractility within and between cells are essential, yet, the role that membrane remodeling may play remains less clear. To clarify how surface turnover and dynamics may modulate tissue arrangements we studied epiboly in the zebrafish. During epiboly the blastoderm expands as a result of an asymmetry of mechanical tension along the embryo surface. In this scenario, we found that the membrane removal by macropinocytosis of the external yolk cell syncytial layer (E-YSL) ahead of the blastoderm is key for epiboly progression In early zebrafish embryos, the activity of the GTPase Rab5ab was essential for endocytosis, and interference in its expression exclusively in the yolk cell resulted in the reduction of yolk cell actomyosin contractility, the disruption of cortical and internal yolk flows, a disequilibrium in force balance and as a result epiboly impairment. We conclude that regulated membrane remodeling is crucial for directing cell and tissue mechanics and coordinating morphogenetic movements during epiboly.

developmental biology↗

bioRxiv2016

The Dachsous/Fat/Four-jointed pathway implements axial long-range cell orientation

Despite a cumulative body of knowledge describing short-range cell interactions in morphogenetic processes, relatively little is known on the mechanism involved in the long-range spatial and temporal coordination of cells to build functional and structurally organized tissues. In particular, the attainment of a functionally optimized epithelia must require directional cues to instruct cell movements and cell orientations throughout the tissue field. In Drosophila, the adult epidermis of the abdominal segments is created de novo by the replacement of obsolete larval epidermal cells (LECs) by histoblasts (imaginal founder cells). As these proliferate, expand and fuse, they uniformly organize orienting on the surface along the antero-posterior axis. We found that the coordinated, axially oriented changes in shape of histoblasts respond to a dynamic, yet stereotyped redesign of the epithelial field mediated by the Dachsous/Fat/Four-jointed (Ds/Ft/Fj) pathway. The establishment and refinement of the expression gradients of the atypical cadherins Ds and Ft result in their axial polarization across cell interfaces and differential adhesiveness. We suggest that the role of Ds/Ft/Fj in long-range axially oriented planar cell alignment is a general function and that the regulation of the expression of its components would be crucial in the achievement of tissue uniformity in many other morphogenetic models or during tissue repair.

developmental biology↗

bioRxiv2016

The architectural balance of the Ventral Nerve Cord depends on the level of JNK signaling activity

Central Nervous System (CNS) organogenesis is a complex process that obeys precise architectural rules. The impact that nervous system architecture may have on its functionality remains, however, relatively unexplored. To clarify this problem, we analyzed the development of the Drosophila embryonic Ventral Nerve Cord (VNC). VNC morphogenesis requires the tight control of Jun kinase (JNK) signaling, exerted in part via a negative feedback loop mediated by the dual specificity phosphatase Puckered, in a subset of pioneer neurons. Here we show that the JNK pathway autonomously regulates neuronal electrophysiological properties without affecting synaptic vesicle transport. Manipulating, during early embryogenesis, JNK signaling activity in pioneer neurons, directly influences their function as organizers of VNC architecture and, moreover, uncovers a role in the coordination of the embryonic motor circuitry that is required for hatching. Together, our data reveal critical links, mediated by the control of the JNK signaling cascade by Puckered, between the structural organization of the VNC and its functional optimization.

developmental biology↗