Biomedical subjects

Roberto Fiore

Publications and source records attributed to Roberto Fiore.

4 recordsLinked to original sources

PubMed2005

Dual functional activity of semaphorin 3B is required for positioning the anterior commissure.

Chemorepulsion by semaphorins plays a critical role during the development of neuronal projections. Although semaphorin-induced chemoattraction has been reported in vitro, the contribution of this activity to axon pathfinding is still unclear. Using genetic and culture models, we provide evidence that both attraction and repulsion by Sema3B, a secreted semaphorin, are critical for the positioning of a major brain commissural projection, the anterior commissure (AC). NrCAM, an immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F. Finally, we show that activation of the FAK/Src signaling cascade distinguishes Sema3B-mediated attractive from repulsive axonal responses of neurons forming the AC, revealing a mechanism underlying the dual activity of this guidance cue.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system.

The semaphorins are a large family of proteins involved in the patterning of both the vascular and the nervous systems. In order to analyze the function of the membrane-bound semaphorin 5A (Sema5A), we generated mice homozygous for a null mutation in the Sema5a gene. Homozygous null mutants die between embryonic development days 11.5 (E11.5) and E12.5, indicating an essential role of Sema5A during embryonic development. Mutant embryos did not show any morphological defects that could account for the lethality of the mutation. A detailed analysis of the vascular system uncovered a role of Sema5A in the remodeling of the cranial blood vessels. In Sema5A null mutants, the complexity of the hierarchically organized branches of the cranial cardinal veins was decreased. Our results represent the first genetic analysis of the function of a class 5 semaphorin during embryonic development and identify a role of Sema5A in the regional patterning of the vasculature.

Animals↗

PubMed2004

Semaphorin 3A stimulates neurite extension and regulates gene expression in PC12 cells.

The secreted semaphorin 3A (Sema3A) is a member of a large family of proteins that act as guidance signals for axons and dendrites. While the receptors and signaling pathways that mediate the repulsive effects of semaphorins are beginning to be understood in some detail, the mechanisms that are responsible for the ability of Sema3A to stimulate the extension of dendrites remain to be elucidated. Here we show that PC12 cells, a model widely used to study neuronal differentiation, can be used to dissect this pathway. Sema3A is as effective as nerve growth factor in stimulating the extension of neurites from PC12 cells. We show that Sema3A is able to regulate gene expression and identify mitochondria as a novel target of Sema3A signaling. Pharmacological block of mitochondrial reactive oxygen species production abolishes the extension of neurites in response to Sema3A. These results show that the characterization of transcripts that are regulated by axon guidance signals may help to identify novel components of their signaling pathways.

Animals↗

PubMed2003

The function of semaphorins during nervous system development.

The wiring of the nervous system is established through a progressive refinement of the choices made by a growing axon. The growth cone is a highly motile structure at the tip of the axon that integrates the multitude of signals present in its environment and translates these signals into structural changes of the cytoskeleton that determine the rate and direction of extension. Four families of guidance cues were identified that provide directional information to growing axons: the ephrins, the netrins, the slit proteins, and the semaphorins. The semaphorins represent the largest family of guidance cues identified so far that can be divided into 8 classes based on the degree of sequence similarity between their semaphorin domains and the presence of class specific carboxy-terminal domains (CTD). Collectively, the in vitro data indicate that semaphorins function mainly as chemorepellents that direct axons away from tissues marked by their expression, but can also act as chemoattractants in some cases. Genetic analysis of the semaphorins and their receptor showed that these proteins play an important role in the development and function of different tissues other than the nervous system. The effects of the different semaphorins are mediated by a variety of receptor complexes that include members of the neuropilin and plexin protein families as well as other membrane proteins belonging to the immunoglobulin superfamily. Plexins directly and indirectly interact with members of the Rho-like GTPases, the kinases Fes, Fyn, and Cdk5, the oxidoreductase MICAL, lipoxygenase, and the CRMP proteins. The signal transduction cascades that include these signalling proteins and link semaphorin receptors to the cytoskeleton are still incompletely understood.

Animals↗