An expression atlas of chemosensory ionotropic glutamate receptors identifies a molecular basis of carbonation detection

Taste perception is thought to involve the encoding of appetitive and aversive chemical cues in food through a limited number of sensory pathways. Through expression analysis of the complete repertoire of Drosophila Ionotropic Receptors (IRs), a sensory subfamily of ionotropic glutamate receptors, we reveal that the majority of IRs is expressed in diverse peripheral neuron populations across gustatory organs in both larvae and adults, implying numerous roles in taste-evoked behaviours. We characterise Ir56d, which labels two anatomically-distinct classes of neurons in the proboscis: one represents a subset of sugar- and fatty acid-sensing neurons, while the other responds to carbonated solutions and fatty acids. Mutational analysis shows that IR56d, together with the broadly-expressed co-receptors IR25a and IR76b, is essential for physiological activation by carbonation and fatty acids, but not sucrose. We further demonstrate that carbonation is behaviourally attractive to flies (in an IR56d-dependent manner), but in a distinct way to other appetitive stimuli. Our work provides a valuable toolkit for investigating the taste functions of IRs, defines a molecular basis of carbonation sensing, and illustrates how the gustatory system uses combinatorial expression of sensory receptors in distinct neuron types to coordinate behaviour

Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons

CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH+) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1+ mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1+ cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH+ cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH+ cells in the IZ close to the midline. Analysis of Cxcr4-/- mice revealed the presence of VM TH+ cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH+ cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.This work was funded by the Swedish Research Council [VR projects: DBRM, 2008:2811, 2011-3116 and 2011-3318]; by the Swedish Foundation for Strategic Research (SRL program); by the Knut and Alice Wallenberg Foundation (CLICK); by the European Commission (NeuroStemcell and DDPD-Genes) and Karolinska Institutet (SFO Thematic Center in Stem cells and Regenerative Medicine) to E.A.; and by the European Commission [mdDANeurodev 222999] to O.M. S.Y. was supported by grants from KID and Chinese Scholarship Council.Peer reviewe

CXCL12-mediated murine neural progenitor cell movement Requires PI3Kß activation

The migratory route of neural progenitor/precursor cells (NPC) has a central role in central nervous system development. Although the role of the chemokine CXCL12 in NPC migration has been described, the intracellular signaling cascade involved remains largely unclear. Here we studied the molecular mechanisms that promote murine NPC migration in response to CXCL12, in vitro and ex vivo. Migration was highly dependent on signaling by the CXCL12 receptor, CXCR4. Although the JAK/STAT pathway was activated following CXCL12 stimulation of NPC, JAK activity was not necessary for NPC migration in vitro. Whereas CXCL12 activated the PI3K catalytic subunits p110α and p110β in NPC, only p110β participated in CXCL12-mediated NPC migration. Ex vivo experiments using organotypic slice cultures showed that p110β blockade impaired NPC exit from the medial ganglionic eminence. In vivo experiments using in utero electroporation nonetheless showed that p110β is dispensable for radial migration of pyramidal neurons. We conclude that PI3K p110β is activated in NPC in response to CXCL12, and its activity is necessary for immature interneuron migration to the cerebral cortex.BLH received an FPI predoctoral fellowship (BES-2006-12965) from the Spanish Ministry of Science and Innovation. This work was supported in part by grants from the Spanish Ministry of Science and Innovation (SAF 2011-27370), the RETICS Program (RD08/0075/0010, RD12/0009/0009; RIER), the Madrid regional government (S2010/BMD-2350; RAPHYME), and the European Union (FP7-integrated project Masterswitch 223404).Peer reviewe

Neurogenetic basis of feeding behavior in Drosophila

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

Chemokine signaling controls intracortical migration and final distribution of GABAergic interneurons

Functioning of the cerebral cortex requires the coordinated assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. Although much is known about the migration of interneurons from the subpallium to the cortex, our understanding of the mechanisms controlling their precise integration within the cortex is still limited. Here, we have investigated in detail the behavior of GABAergic interneurons as they first enter the developing cortex by using time-lapse videomicroscopy, slice culture, and in utero experimental manipulations and analysis of mouse mutants. We found that interneurons actively avoid the cortical plate for a period of ∼48 h after reaching the pallium; during this time, interneurons disperse tangentially through the marginal and subventricular zones. Perturbation of CXCL12/CXCR4 signaling causes premature cortical plate invasion by cortical interneurons and, in the long term, disrupts their laminar and regional distribution. These results suggest that regulation of cortical plate invasion by GABAergic interneurons is a key event in cortical development, because it directly influences the coordinated formation of appropriate glutamatergic and GABAergic neuronal assemblies.This work was supported by Spanish Ministry of Education and Science (MEC) Grants BFU2005-04773/BMC and CONSOLIDER CSD2007-0003, by the Fundació “la Caixa,” by the European Commission through STREP contract number 005139 (INTERDEVO), and by the European Young Investigator (EURYI) program (O.M.); and by Spanish MEC Grant BFU2005-02393 (M.V.). G.L.-B. was a “Ramón y Cajal” Investigator from the Consejo Superior de Investigaciones Científicas (CSIC). R.P. and J.A.S.-A. were supported by Formación de Personal Investigador and Formación de Profesorado Universitario fellowships from the Spanish MEC, respectively. V.B. is a “Ramón y Cajal” Investigator from the CSIC and a recipient of a Human Frontier Science Program Organization Career Development AwardPeer reviewe

Tratamiento de enfermedades causadas por alteraciones del desarrollo axonal de neuronas

Filing Date: 2007-04-03.-- Priority Data: ES P200600882 (2006-04-05).[English] The invention relates to the use of a peptide that comprises the amino acid sequence of the epidermal growth factor-like domain (EGF domain) of neuregulin 1 (NRG1), or a functionally equivalent variant or fragment thereof, or of a polynucleotide that codes for said peptide or functionally equivalent fragment or variant, or of a compound that induces the production and/or activity of said NRG1, in the preparation of a pharmaceutical composition for treating disorders caused by changes in the axonal development of neurones in the nervous system.[Español] La invención se relaciona, en general, con el tratamiento de enfermedades causadas por alteraciones del desarrollo axonal de las neuronas del sistema nervioso, particularmente en humanos, basado en el empleo de la neuregulina 1 (NRG1), o una variante o fragmento funcionalmente equivalente de la misma, o de un polinucleótido que codifica dicha proteína, variante o fragmento funcionalmente equivalente, o de un compuesto que potencia la producción y/o actividad de dicha NRG1.Peer reviewe

Cxcr7 Controls Neuronal Migration by Regulating Chemokine Responsiveness

The chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process.We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Intriguingly, this process does not exclusively involve Cxcr7, but most critically the modulation of Cxcr4 function. Thus, Cxcr7 is necessary to regulate Cxcr4 protein levels, thereby adapting chemokine responsiveness in migrating cells. This demonstrates that a chemokine receptor modulates the function of another chemokine receptor by controlling the amount of protein that is made available for signaling at the cell surface.J.A.S-A. was supported by a fellowship from the FPU program of the Spanish Ministry of Science and Innovation (MICINN). This work was supported by grants from Spanish MICINN SAF2008-00770 and CONSOLIDER CSD2007-00023, and the EURYI scheme award (see www.esf. org/euryi) (to O.M), and by Federal State Sachsen-Anhalt with the European Fund For Regional Development (EFRE 2007-2013) and Deutsche Forschungsgemeinschaft (DFG) grant STU295/5-1 (to R.S).Peer reviewe