Biology subjects

Usieto, S.

Publications and source records attributed to Usieto, S..

5 recordsLinked to original sources

bioRxiv2025

Rootletin Fiber Dynamics Integrate Cytoskeletal Programs to Shape Neuroepithelial Architecture

Central nervous system (CNS) architecture is established early by the organization and proliferative behavior of neuroepithelial (NE) cells, which form a pseudostratified epithelium during neural tube (NT) formation. In neurogenesis, newborn neurons have to detach and exit the neuroepithelium, in a process that requires the coordinated disassembly of apical junctions and the centrosome-cilia module. Although Rootletin--the structural component of the ciliary rootlet and centriolar linker--is classically viewed as a static mechanical element, its behavior in NE cells has not been described in detail. Here, we uncover a conserved, dynamic form of Rootletin fiber organization that remodels in synchrony with NE cell morphogenesis. We show that, in NE cells in interphase, Rootletin fibers extend from the basal body through the apical process toward the nucleus, and that Rootletin maintains its fibrous conformation throughout mitosis. As NE cells initiate apical constriction, Rootletin fibers retract from the apical process and assemble into an anisotropic rim-like structure that aligns with the apical junctional complex. This remodeling is coordinated with microtubule stabilization in low-tension apical endfeet and occurs prior to Lzts1 expression and increased actomyosin contractility. Forced neuronal delamination via Neurogenin-2 or Lzts1 promotes Rootletin rim formation and Rootletin alignment with the apical endfoot cortex. Finally, we show that Zika virus NS5 protein can aberrantly associate with all conformational states of Rootletin fibers, providing a potential mechanical link between ZikaV infection and premature delamination. Together, our findings identify Rootletin as a dynamically regulated cytoskeletal scaffold that orchestrates apical surface remodeling in NE cells and identify a potential mechanism by which ZikaV disrupts neurodevelopment.

developmental biology↗

bioRxiv2021

Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. NBs are known to originate from alterations to cells in the sympatho-adrenal lineage derived from the neural crest, but whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their developmental origin remains unclear. Here, we compared the transcriptional landscapes of primary samples of LR-NBs, HR-NBs and human fetal adrenal gland, and thereby identified the transcriptional signature associated to NB formation that further distinguishes LR-NBs from HR-NBs. The majority of the genes comprising this signature belong to the core sympatho-adrenal developmental program, are associated with favorable patient prognosis and with diminished disease progression. The top candidate gene of this list, Neurexophilin-1 (NXPH1), encodes a ligand of the transmembrane receptors -Neurexins (-NRXNs). Our functional in vivo and in vitro assays reveal that NXPH1/-NRXN signaling has a dual impact on NB behavior: whereas NXPH1 and -NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit the ability of NB cells to form metastases. Our findings uncover a module of the neural crest-derived sympatho-adrenal developmental program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/-NRXN signaling as a promising target to treat HR-NBs.

neuroscience↗

bioRxiv2020

Cell intercalation driven by SMAD3 underlies secondary neural tube formation

Body axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodelling of the tailbud. Although it is clear how bi-potential neuro-mesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead to de novo lumen formation and that culminate in the formation of a 3-Dimensional, secondary neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-beta/SMAD3 signalling is required for secondary neural tube formation. Our analysis describes the initial events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. Importantly, we show that the resolution of a single, centrally positioned continuous lumen, which occurs through the intercalation of central cells, requires SMAD3 activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, amongst the most frequent birth defects detected in humans. HIGHLIGHTS.- Initiation of the lumen formation follows the acquisition of neural identity and epithelial polarization. .- Programmed cell death is not required for lumen resolution. .- Resolution of a single central lumen requires cell intercalation, driven by Smad3 activity .- The outcome of central cell division preceding cell intercalation, varies along the cranio-caudal axis.

developmental biology↗

bioRxiv2019

Evolutionary conserved canonical BMP activity controls cortical neurogenesis

The growth and evolutionary expansion of the cerebral cortex are defined by the spatial-temporal production of neurons, which itself depends on the decision of radial glial cells (RGCs) to self-amplify or to switch to neurogenic divisions. The mechanisms regulating these RGC fate decisions are still incompletely understood. Here we describe a novel and evolutionarily conserved role of the canonical BMP transcription factors SMAD1/5 in controlling neurogenesis and growth during corticogenesis. Reducing the expression of both SMAD1 and SMAD5 in neural progenitors at early mouse cortical development caused microcephaly and an increased production of early-born cortical neurons at the expense of late-born ones, which correlated with the premature differentiation and depletion of the pool of cortical progenitors. Gain- and loss-of-function experiments performed during early cortical neurogenesis in the chick revealed that SMAD1/5 activity supports self-amplifying RGC divisions and restrain the neurogenic ones. Furthermore, we demonstrate that SMAD1/5 stimulate RGC self-amplification through the positive post-transcriptional regulation of the Hippo signaling effector YAP. We anticipate this SMAD1/5-YAP signaling module to be fundamental in controlling growth and evolution of the amniote cerebral cortex.

developmental biology↗

bioRxiv2018

E proteins differentially co-operate with proneural bHLH transcription factors to sharpen neurogenesis

Basic HLH proteins heterodimerize with class I HLH/E proteins to promote transcription. Here we show that E proteins differentially co-operate with proneural bHLH transcription factors sharpening their neurogeneic activity. We find that inhibiting BMP signaling or its target ID2, in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We define the mechanisms of this differential response as a dual co-operation of E proteins with proneural proteins. E proteins synergize with bHLH proteins when acting on CAGSTG motifs, thereby facilitating the neurogenic activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E proteins restrict the strong neurogenic potential of NEUROG1/2 by directly inhibiting their preferential binding to CADATG motifs. Since we find this mechanism to be conserved in corticogenesis, we propose this dual co-operation of E proteins with bHLH proteins as a novel though general feature of their mechanism of action.

developmental biology↗