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Biology subjects

Miguez, D. G.

Publications and source records attributed to Miguez, D. G..

7 recordsLinked to original sources

A signaling network motif couples protein expression levels and intracellular localization

Most of the accepted major signaling pathways incorporate a mechanism of physical separation of active versus inactive effector proteins, in the form of dynamic nucleocytoplasmic shuttling. Here, we show that when this translocation takes place as dimers, it operates as a network motif that introduces a nonlinear coupling between expression levels of a protein and its intracellular localization. This mechanism modulates the activity of the TGF-{beta} signaling cascade by affecting the location of its main effectors, the R-Smads, as well as in all signaling cascades analyzed that incorporate a dimerization step linked to nucleocytoplasmic shuttling, operating as a singular type of nonlinear network motif that does not require a loop of regulation and takes advantage of physical intracellular compartmentalization.

systems biology↗

The V-ATPase/ATG16L1 axis drives membrane remodeling during epithelial morphogenesis

Epithelial tubulogenesis shapes internal organs by transforming flat epithelial sheets or unpolarized cords into hollow tubes with central lumens. A key example is the formation of the posterior neural tube during secondary neurulation, which requires precise morphogenetic events for de novo lumen formation. Although several studies have highlighted the role of autophagy in specific morphogenetic events, its involvement in epithelial organ development remains unclear. Autophagy operates via canonical and noncanonical pathways. Canonical autophagy is catabolic, requiring double-membrane autophagosomes and the full ATG protein set. Noncanonical autophagy, including the V-ATPase/ATG16L1-dependent Conjugation of ATG8 in Single Membranes (CASM), has both degradative and non-degradative roles and regulates different membrane trafficking processes. Using human neural tube organoids, spheroids, and tube micropatterns deficient in CASM or canonical autophagy, we show that CASM plays a pivotal role in epithelial tube morphogenesis. Specifically, the V-ATPase/ATG16L1 axis is essential for de novo lumen formation by regulating membrane junction remodeling and Rab11-dependent recycling pathways. These findings reveal distinct contributions of autophagy pathways in epithelial development, with potential implications for diseases linked to autophagy dysfunction.

cell biology↗

High-throughput three-dimensional characterization of morphogenetic signals during the formation of the vertebrate retina

The balance between self-renewal and terminal differentiation of neural progenitors is regulated by a complex interplay of signaling pathways that set the spatial and temporal cues that ultimately shape and organize neurogenic tissues. In this contribution, we combine in toto experiments with three-dimensional image analysis, computational modeling, and theoretical tools to provide a quantitative characterization of the dynamics of growth and differentiation of the developing vertebrate retina. We show that the tissue develops by gradually increasing the average rate of differentiation and reducing the average cell cycle length. Moreover, this balance between differentiation and cell cycle duration increases the yield of production of terminally differentiated neurons, and it is required to achieve a well-defined exponential growth. We also show that a potential regulator of this balance is Hedgehog (Hh), promoting simultaneously cell cycle progression and cell cycle exit of RPCs. Our results represent a detailed and accurate quantitative characterization of retinal neurogenesis and how signals regulate the balance between proliferation and differentiation during the development of the vertebrate retina.

systems biology↗

Midbody remnant inheritance is regulated by the ESCRT subunit CHMP4C

The inheritance of the midbody remnant (MBR) breaks the symmetry of the two daughter cells, with functional consequences for lumen and primary cilium formation by polarized epithelial cells, and also for development and differentiation. However, despite their importance, neither the relationship between the plasma membrane and the inherited MBR nor the mechanism of MBR inheritance is well known. Here, the analysis by correlative light and ultra-high-resolution scanning electron microscopy reveals a membranous stalk that physically connects the MBR to the apical membrane of epithelial cells. The stalk, which derives from the uncleaved side of the midbody, concentrates the ESCRT machinery. The ESCRT CHMP4C subunit enables MBR inheritance, and its depletion dramatically reduces the percentage of ciliated cells. We demonstrate: (1) that MBRs are physically connected to the plasma membrane, (2) how CHMP4C helps maintain the integrity of the connection, and (3) the functional importance of the connection.

cell biology↗

Radial Glial from mammalian developing neocortex can divide symmetrically in vitro

Radial Glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well known ability to expand in number when cultured in vitro, driven by Fibroblast Growth Factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here we combine experiments of Radial Glia cultures with theory and numerical models to show that Fibroblast Growth Factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. This combined effect of Fibroblast Growth Factor 2 in the differentiation dynamics of Radial Glial progenitors partner to establish and sustain a pool of rapidly proliferating in vitro pool of Radial Glial progenitors.

developmental biology↗

Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks

Forces generated by the actomyosin cytoskeleton are key contributors to the generation of tissue shape. Within the cell, the actomyosin cytoskeleton organizes in different types of networks, each of them performing distinct roles. In addition, although they normally localize to precise regions of the cells, they are rarely independent and often their dynamics influence each other. In fact, the reorganization of a given structure can promote the formation of another, conversions that govern many morphogenetic processes. In addition, maintenance of a specific actomyosin network organization in a differentiated tissue might be equally important. Failure to do so could lead to undesired cell state transitions, which in turn would have drastic consequences on the homeostasis of the tissue. Still, little is known about the mechanisms that ensure controlled transitions between actomyosin networks during morphogenesis or their maintenance in a differentiated tissue. Here, we use the Drosophila follicular epithelium to show that cell-ECM interactions mediated by integrins are necessary for the establishment and maintenance of the different actomyosin networks present in these epithelial cells. Elimination of integrins in a group of follicle cells results in changes in the F-actin levels and physical properties of their intracellular actomyosin networks. Integrin mutant follicle cells have reduced number of basal stress fibers. They also show increased cortical F-actin levels and tension, which interferes with proper basal surface growth. Finally, clonal elimination of integrins also triggers non-autonomous behavioural changes in neighbouring wild types cells, which now reorganize their actin cytoskeleton and spread and overlay the mutant ones. Based on these results, we propose that cell-ECM interactions mediated by integrins regulate epithelia morphogenesis and homesostasis by preserving the different types of intracellular actin networks.

cell biology↗

Dynamic Hh signaling can generate temporal information during tissue patterning

The differentiation of tissues and organs requires that cells exchange information in space and time. Spatial information is often conveyed by morphogens, molecules that disperse across receiving cells generating signaling gradients. Cells translate such concentration gradients into space-dependent patterns of gene expression and cellular behavior [1, 2]. But could morphogen gradients also convey developmental time? Here, investigating the developmental role of Hh on a component of the Drosophila visual system, the ocellar retina, we discovered that ocellar cells use the non-linear gradient of Hh as a temporal cue, collectively performing the biological equivalent of a mathematical logarithmic transformation. In this way, a morphogen diffusing from a non-moving source is decoded as a wave of differentiating photoreceptors that travels at constant speed throughout the retinal epithelium.

developmental biology↗