A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5 and 7 but not Hdac9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4,5 and 7 are simultaneously removed, the Myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury

Nuevo servicio microscopia electrónica ISABIAL

Póster presentado al Encuentro de Investigación: Buscando Sinergias, celebrado el 7 de junio de 2022 en el Salón de Actos del Hospital General Dr. Balmis (Alicante).Peer reviewe

Oligomerization of the sensory and motor neuron-derived factor prevents protein O-glycosylation

The sensory and motor neuron-derived factor (SMDF) is a neuregulin that promotes Schwann cell proliferation and differentiation. Hence, understanding axon myelination is important to unveil the mechanisms involved in SMDF biogenesis, membrane delivery, and compartmentalization. SMDF is a type II membrane protein expressed as two distinct polypeptides of ∼40 and 83 kDa. Whether the 83-kDa polypeptide results from posttranslational modifications of the protein monomers or protein dimerization remains unknown. Here we have addressed this question and shown that the 83-kDa polypeptide is an O-glycosylated form of the protein. Deletion of the N-terminal domain fully abrogates the SMDF O-glycosylation, indicating that incorporation of O-glycans occurs in the intracellular domain of the protein. Notably, O-glycosylated forms are excluded from partitioning into lipid raft microdomains. In addition, we found that heterologously expressed SMDF monomers interact in intact living cells as evidenced from fluorescence resonance energy transfer of cyan fluorescent protein/yellow fluorescent protein·SMDF fusion proteins. A stepwise deletion approach demonstrated that SMDF self-association is primarily determined by its transmembrane segment. Notably, biochemical analysis revealed that SMDF multimers are exclusively composed of the 40-kDa polypeptide. Collectively, these findings indicate that the 40-kDa form corresponds to unmodified SMDF, which may be present as multimers, whereas the 83-kDa polypeptide is a monomeric O-glycosylated form of the protein. Furthermore, our observations imply a role for oligomerization as a potential modulator of the distribution in membrane domains and O-glycosylation of the protein.This work was supported by Grant FIS01/3081 from the Instituto de Salud CarlosIII and Beca SeveroOchoa2002 from the Fundacion PrincipedeAsturias(toH.C.), by GrantSAF2003-0509 fromthe SpanishMinistryofScienceandTechnology(MCYT), and by GrantFIS-01/ 1162 from theInstitutodeSaludCarlosIII and Grant01/085-00from the FundacionLaCaixa(toA.F.-M.). Recipientofapredoctoral FormaciondeProfesoradoUniversitario (FPU) fellowshipfromthe SpanishMinistryofEducation,Culture,and Sports.Peer reviewe

Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival

In collection: Ubiquitin and Protein Degradation.Neuregulins are a family of genes involved in key aspects of neural biology. Neuregulins 1, 2 and 3 (NRG1, NRG2 and NRG3) are expressed in the mammalian nervous system. It is well established that NRG1, with fifteen different splicing forms, is central for brain development and function. However, the biological relevance of NRG2 and NRG3 remains elusive. Here, we report the identification of a new isoform of NRG3 that is specifically expressed in the human embryonic central nervous system. Sequence alignment with the human genome suggests that this transcript is produced by alternative promoter usage. The encoded polypeptide is a type-I-glycosylated plasma membrane protein, which is shed into the extracellular space where it activates erbB4, a pivotal receptor for brain development. In addition, we show that the protein has a signal sequence that is cleaved after membrane insertion. Proteasome inhibition with Lactacystin enhances the expression of the protein, whereas impairment of ubiquitylation in the conditional mutant cell line ts20 protects the protein from degradation. These observations imply that the ubiquitin/proteasome pathway regulates biogenesis of the protein. We also show that recombinant neuregulin 3 acts as an oligodendrocyte survival factor by activating the phosphoinositide 3-kinase signalling pathway. Therefore, we report a new post-translationally regulated isoform of neuregulin 3 expressed in the developing human central nervous system with a role in oligodendrocyte survival.C.C. holds a predoctoral FPU fellowship from the Spanish Ministry of Education and Science. This work was supported by grants from `Instituto de Salud Carlos III' (FIS 01/3081) and `Fundación Principe de Asturias' (Beca Severo Ochoa 2002) to H.C., and from MEC (SAF 2003-0509) to A.F.M.Peer reviewe

Class IIa HDACs in myelination

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License.Peer reviewe

L1CAM binds ErbB receptors through Ig-like domains coupling cell adhesion and neuregulin signalling

During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM. © 2012 Donier et al.This work has been funded by grants PROMETEO 2008/134 (Conselleria Educació Generalitat Valenciana) to LGA and HC and SAF2008-04106 (Spanish MICINN) to HC. JL holds a Junta para la Ampliación de Estudios (JAE) Programme/Spanish National Research Council (CSIC) pre-doctoral fellowship.Peer Reviewe

Transcriptional control of cholesterol biosynthesis in schwann cells by axonal neuregulin 1

A characteristic feature of many vertebrate axons is their wrapping by a lamellar stack of glially derived membranes known as the myelin sheath. Myelin is a cholesterol-rich membrane that allows for rapid saltatory nerve impulse conduction. Axonal neuregulins instruct glial cells on when and how much myelin they should produce. However, how neuregulin regulates myelin sheath development and thickness is unknown. Here we show that neuregulin receptors are activated by drops in plasma membrane cholesterol, suggesting that they can sense sterol levels. In Schwann cells neuregulin-1 increases the transcription of the 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. Neuregulin activity is mediated by the phosphatidylinositol 3-kinase pathway and a cAMP-response element located on the reductase promoter. We propose that by activating neuregulin receptors, neurons exploit a cholesterol homeostatic mechanism forcing Schwann cells to produce new membranes for the myelin sheath. We also show that a strong phylogenetic correlation exists between myelination and cholesterol biosynthesis, and we propose that the absence of the sterol branch of the mevalonate pathway in invertebrates precluded the myelination of their nervous system.This work was supported in part by Spanish Ministry of Education and Science Grant SAF2004-01011 (to F. V.), “Instituto de Salud Carlos III” Grant PI05/0535, and “Conselleria de Salut de la Generalitat Valenciana” Grant AP-002/06 (to H. C.).Peer reviewe