Biomedical subjects

Fernando de Castro

Publications and source records attributed to Fernando de Castro.

7 recordsLinked to original sources

PubMed2026

Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.

Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.

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PubMed2006

Anosmin-1 modulates the FGF-2-dependent migration of oligodendrocyte precursors in the developing optic nerve.

Oligodendrocyte precursors (OPCs) originate at specific domains within the neural tube before migrating to colonize the entire CNS. Once in their target areas, these cells differentiate into oligodendrocytes, the myelin-forming cells in the CNS. Using the embryonic mouse optic nerve as an experimental model, we have analyzed the influence of FGF-2 on OPC development. FGF-2 exerts a dose-dependent motogenic effect on the migration of plp-dm20+ and it also acts as a chemoattractant on these cells. These effects produced by FGF-2 are principally mediated by the FGFR1 receptor, which is expressed by OPCs. Anosmin-1 is the protein that is defective in the X-linked form of human Kallmann syndrome. This protein is expressed by retinal axons and it also interacts with FGFR1, thereby impairing the migration of OPCs. Because both Anosmin-1 and FGF-2 are present in the optic nerve in vivo, we propose a model whereby the relative concentration of these two proteins modulates the migration of OPCs during development through their interaction with FGFR1. This FGF-2/FGFR1/Anosmin-1 system may be relevant in the context of demyelinating diseases.

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PubMed2006

Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells.

During the embryonic period, many olfactory bulb (OB) interneurons arise in the lateral ganglionic eminence (LGE) from precursor cells expressing Dlx2, Gsh2 and Er81 transcription factors. Whether GABAergic and dopaminergic interneurons are also generated within the embryonic OB has not been studied thoroughly. In contrast to abundant Dlx2 and Gsh2 expression in ganglionic eminences (GE), Dlx2 and Gsh2 proteins are not expressed in the E12.5-13.5 mouse OB, whereas the telencephalic pallial domain marker Pax6 is abundant. We found GABAergic and dopaminergic neurons originating from dividing precursor cells in E13.5 OB and in short-term dissociated cultures prepared from the rostral half of E13.5 OB. In OB cultures, 22% of neurons were GAD+, of which 53% were Dlx2+, whereas none expressed Gsh2. By contrast, 70% of GAD+ cells in GE cultures were Dlx2+ and 16% expressed Gsh2. In E13.5 OB slices transplanted with EGFP-labeled E13.5 OB precursor cells, 31.7% of EGFP+ cells differentiated to GABAergic neurons. OB and LGE precursors transplanted into early postnatal OB migrated and differentiated in distinct patterns. Transplanted OB precursors gave rise to interneurons with dendritic spines in close proximity to synaptophysin-positive boutons. Interneurons were also abundant in differentiating OB neural stem cell cultures; the neurons responded to the neurotrophin Bdnf and expressed presynaptic proteins. In vivo, the Bdnf receptor TrkB colocalized with synaptic proteins at the glomeruli. These findings suggest that, in addition to receiving interneurons from the LGE, the embryonic OB contains molecularly distinct local precursor cells that generate mature GABAergic and dopaminergic neurons.

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PubMed2005

The molecular orchestra of the migration of oligodendrocyte precursors during development.

During development of the central nervous system (CNS), postmitotic cells (including neurons and myelin-generating cells, the oligodendrocytes) migrate from the germinal areas of the neural tube where they originate to their final destination sites. The migration of neurons during development has been extensively studied and has been the topic of detailed reviews. The migration of oligodendrocyte precursor cells (OPCs) is also an extremely complex and precise event, with a widespread migration of OPCs across many regions to colonize the entire CNS. Different mechanisms have been shown to direct the migration of OPCs, among them contact-mediated mechanisms (adhesion molecules) and long-range cues (chemotropic molecules). This review provides a detailed overview and discussion of the cellular and molecular basis of OPCs migration during development. Because it has been shown that neuronal and oligodendroglial lineages share some of these mechanisms, we briefly summarize similarities and differences between these two types of neural cells. We also summarize the changes in the normal migration of OPCs during development that would be relevant for different neurological diseases (including demyelinating diseases, such as multiple sclerosis, and glial cancers). We also examine the relevance of these migratory properties of the oligondendrocytic cell lineage for the repair of neural damage.

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PubMed2003

Chemotropic molecules: guides for axonal pathfinding and cell migration during CNS development.

Different molecules (netrins, semaphorins, slits) with chemotropic functions and their receptors (neogenin, DCC, neuropilins, plexins, robos) have been identified that guide axons during development of the nervous system to establish the complex pattern of connections among a large number of neurons. These molecules have been recently identified to play a role in cell migration of the central nervous system during development.

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PubMed2002

Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1.

Oligodendrocytes, the myelin-forming cells of the CNS, are generated from multiple foci distributed along the developing neural tube. Little is known about the endogenous guidance cues controlling the migration of oligodendrocyte precursor cells (OPCs) from their site of emergence toward their final destination, mainly the future white matter tracts. During embryonic development, the optic nerve is populated by OPCs originating in the diencephalon that migrate from the chiasm toward the retina. Here we show that OPCs migrating into the embryonic optic nerve express the semaphorin receptors neuropilin-1 and -2, as well as deleted in colorectal cancer (DCC) and, to a lesser extend unc5H1, two of the netrin-1 receptors. Using a functional migration assay, we provide evidence that Sema 3A and netrin-1 exert opposite chemotactic effects, repulsive or attractive, respectively, on embryonic OPCs. In addition, we show that Sema 3F has a dual effect, chemoattractive and mitogenic on embryonic OPCs. The localization of cells expressing Sema 3A, Sema 3F, and netrin-1 is consistent with a role for these ligands in the migration of OPCs in the embryonic optic nerve. Altogether, our results suggest that the migration of OPCs in the embryonic optic nerve is modulated by a balance of effects mediated by members of the semaphorin and netrin families.

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PubMed2002

Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons.

The physiological role of anosmin-1, defective in the X chromosome-linked form of Kallmann syndrome, is not yet known. Here, we show that anti-anosmin-1 antibodies block the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhances axonal branching of these dissociated neurons in culture. In addition, coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrate that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. We conclude that anosmin-1 has a dual branch-promoting and guidance activity, which plays an essential role in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex.

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