Hijacking of Embryonic Programs by Neural Crest-Derived Neuroblastoma: From Physiological Migration to Metastatic Dissemination

In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards appropriate territories, eliminate superfluous cells, and induce terminal differentiation of survivors into the appropriate cell-types. Despite strict controls constraining developmental processes, malignancies can emerge in still immature organisms. This is the case of neuroblastoma (NB), a highly heterogeneous disease, predominantly affecting children before the age of 5 years. Highly metastatic forms represent half of the cases and are diagnosed when disseminated foci are detectable. NB arise from a transient population of embryonic cells, the neural crest (NC), and especially NC committed to the establishment of the sympatho-adrenal tissues. The NC is generated at the dorsal edge of the neural tube (NT) of the vertebrate embryo, under the action of NC specifier gene programs. NC cells (NCCs) undergo an epithelial to mesenchymal transition, and engage on a remarkable journey in the developing embryo, contributing to a plethora of cell-types and tissues. Various NCC sub-populations and derived lineages adopt specific migratory behaviors, moving individually as well as collectively, exploiting the different embryonic substrates they encounter along their path. Here we discuss how the specific features of NCC in development are re-iterated during NB metastatic behaviors

Plum pudding random medium model of biological tissue toward remote microscopy from spectroscopic light scattering

Biological tissue has a complex structure and exhibits rich spectroscopic behavior. There is \emph{no} tissue model up to now able to account for the observed spectroscopy of tissue light scattering and its anisotropy. Here we present, \emph{for the first time}, a plum pudding random medium (PPRM) model for biological tissue which succinctly describes tissue as a superposition of distinctive scattering structures (plum) embedded inside a fractal continuous medium of background refractive index fluctuation (pudding). PPRM faithfully reproduces the wavelength dependence of tissue light scattering and attributes the "anomalous" trend in the anisotropy to the plum and the powerlaw dependence of the reduced scattering coefficient to the fractal scattering pudding. Most importantly, PPRM opens up a novel venue of quantifying the tissue architecture and microscopic structures on average from macroscopic probing of the bulk with scattered light alone without tissue excision. We demonstrate this potential by visualizing the fine microscopic structural alterations in breast tissue (adipose, glandular, fibrocystic, fibroadenoma, and ductal carcinoma) deduced from noncontact spectroscopic measurement

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy

GPC3-Unc5 receptor complex structure and role in cell migration

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration

Interactions entre sémaphorines de classe III et molécules d'adhérence de la super famille des immunoglobulines dans le guidage axonal

Les axones possèdent un cône de croissance qui intègre les effets répulsifs et attractifs de signaux environnementaux pour se diriger vers leurs tissus cibles. La Semaphorine3A repousse les cônes de croissance par l activation d un complexe récepteur formé de la Neuropiline-1 qui lie le ligand, et d une Plexin-A, qui contrôle le remodelage du cytosquelette d actine. Un troisième partenaire a été identifié, la molécule d adhérence (IgCAM) L1, dont la fonction reste inconnue. Nous avons démontré la participation d une nouvelle IgCAM au complexe récepteur de deux autres Sémaphorines. Puis, nous avons montré que la sous-unité IgCAM contrôle un processus nécessaire à la réponse répulsive aux Sémaphorines, qui est le désassemblage des contacts adhérents entre les cônes de croissance et leur substratAxons elaborate growth cones, which integrate repulsive and attractive effects of environmental guidance cues to reach their target tissue. The Semaphorin3A repels the growth cones by activating a receptor complex composed of Neuropilin-1, the ligand binding sub-unit, and Plexin-A controlling the cytoskeleton remodeling. The cell adhesion molecule (IgCAM) L1 was found as a third partner of this complex, but its function remains unknown. We identified an IgCAM partner in the receptor complex of two other Semaphorins and demonstrated its implication in their guidance function. We investigated the role of L1 in the Sema3A receptor and found that it controls a crucial process of the repulsive behavior, which is the disassembly of adherent contacts between growth cones and their substrateLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Control of semaphorin signaling.

Receptor complexes for the chemorepellent factors of the semaphorin family activate intracellular pathways that trigger actin rearrangements underlying growth cone collapse and repellent behavior. Some evidence has been provided for a complex and dynamic pattern of interaction between members of the small Rho guanosine triphosphatases and plexin proteins that are the receptor subunits responsible for initiating semaphorin signaling. The characterization of new components of semaphorin receptor complexes, the implication of several distinct classes of cytoplasmic effectors, together with the observation of a variety of processes modulating the semaphorin signal have provided a basis for a much improved, but still intricate view of the semaphorin transduction pathways in neurons

Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM.

During axon navigation, Semaphorin3A-induced growth cone retraction is correlated with endocytosis. Although its function remains elusive, we showed previously that the cell adhesion molecule of the immunoglobulin super family L1 associates with Neuropilin-1 (NP-1) the Sema3A-binding subunit of the receptor complex and is required for Sema3A to elicit axonal repulsive responses. We report here that upon Sema3A binding to NP-1, L1 and NP-1 are co-internalized through a clathrin-dependent mechanism mediated by L1. We show that in COS7 cells, L1/NP-1 endocytosis is correlated with a cell contraction similar to that observed with the Plexin (Plex)/NP-1 or Plex/NP1/L1 complexes. In neuronal cultures, a L1-mimetic peptide able to switch Sema3A repulsive responses to attraction blocks both endocytosis and growth cone collapse. Similarly, in the COS7 cell model, peptide application prevents both the Sema3-induced L1/NP-1 internalization and cell collapse. These studies demonstrate that the L1/NP-1 complex is able to confer a biological response to Sema3A with L1 mediating receptor internalization following ligand activation. They also reveal that endocytosis controlled by L1/NP-1 cis and trans interactions is pivotal in Sema3A-mediated axon guidance