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PMID:16807322 ; Functioning of the cerebral cortex requires the coordinated assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. Despite their segregated origin in different regions of the telencephalon, projection neurons and interneurons born synchronically end up adopting the same cortical layer, suggesting that layer acquisition is highly coordinated for both neuronal types. The radial migration and laminar arrangement of projection neurons depends on Reelin, a secreted glycoprotein expressed near the pial surface during embryogenesis. In contrast, the mechanisms controlling layer acquisition by cortical interneurons remain essentially unknown. Here, we have used an ultrasound-guided transplantation approach to analyze the mechanisms underlying the acquisition of laminar locations by cortical interneurons. We found that layer acquisition by cortical GABAergic interneurons does not directly depend on Reelin signaling. Moreover, interneurons invade their target layers well after synchronically generated projection neurons reach their final destination. These results suggest a model in which cues provided by projection neurons guide cortical interneurons to their appropriate layer, and reveal that, at least for some neuronal types, long-range radial migration does not directly require Reelin. ; This work was supported by grants to O.M. from the Spanish Government (BFU2005-04773/BMC), fundació "la Caixa," the European Commission through STREP contract number 005139 (INTERDEVO), and the European Young Investigator Award (EURYI) program. R.P. was supported by a Formación de Personal Investigator fellowship from the Spanish Ministerio de Educación y Ciencia (MEC). V.B. is a "Ramón y Cajal" Investigator from the Consejo Superior de Investigaciones Científicas. N.F. was supported by a Formación de Profesorado Universitario fellowship from the Spanish MEC. O.M. is a European Molecular Biology Organization Young Investigator, a National Alliance for Research on Schizophrenia and Depression Young Investigator, and an EURYI Awardee. We thank T. Gil, M. Pérez, and M. Bonete for excellent technical assistance; B. Condie, V. Pachnis, and J. L. R. Rubenstein for plasmids and reagents; and G. D'Arcangello and K. Campbell for providing Dab1 and Dlx5/6CRE-IRES-GFP mice, respectively. ; Peer reviewed

24 páginas, 7 figuras. Borras C, et al. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi:10.18632/aging.101078. ; Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging. ; This work was supported by grants SAF2013-44663-R, from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029 from the "Red Tematica de investigacion cooperative en envejecimiento y fragilidad" (RETICEF); PROMETEOII/2014/056 from "Conselleria d'Educació, Cultura I Esport de la Generalitat Valenciana"; and EU Funded CM1001 and FRAILOMIC-HEALTH.2012.2.1.1-2 (To J.V) APM-03/15 from Conselleria de Sanitat, AICO/2016/067 and from Conselleria d'Educació, Cultura i Esport de la Generalitat Valenciana, Intramural Grant from INCLIVA (to C.B.),VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.) and Marie Curie Career Integration Grant (to N.F). This study has been co-financed by FEDER funds from the European Union. ; Peer reviewed

25 páginas, 8 figuras. ; During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling. ; NF research is funded by European ResearcPRE2018-086h Council (ERC StG 281920; ERC COG 101002203), Spanish Government (SAF2017-84790-R) and Generalitat Valenciana (PROMETEO/2018/055). A.M.T holds the PRE2018-086632 fellowship from Spanish Government and A.J the ACIF/2015/398 fellowship from Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer reviewed

The mammalian telencephalon is considered the most complex of all biological structures. It comprises a large number of functionally and morphologically distinct types of neurons that coordinately control most aspects of cognition and behavior. The subpallium, for example, not only gives rise to multiple neuronal types that form the basal ganglia and parts of the amygdala and septum but also is the origin of an astonishing diversity of cortical interneurons. Despite our detailed knowledge on the molecular, morphological, and physiological properties of most of these neuronal populations, the mechanisms underlying their generation are still poorly understood. Here, we comprehensively analyzed the expression patterns of several transcription factors in the ventricular zone of the developing subpallium in the mouse to generate a detailed molecular map of the different progenitor domains present in this region. Our study demonstrates that the ventricular zone of the mouse subpallium contains at least 18 domains that are uniquely defined by the combinatorial expression of several transcription factors. Furthermore, the results of microtransplantation experiments in vivo corroborate that anatomically defined regions of the mouse subpallium, such as the medial ganglionic eminence, can be subdivided into functionally distinct domains. ; This work was supported by grants from the Spanish Government (BFU2005-04773/BMC), Fundació "la Caixa," the European Commission through Specific Targeted Research Project Contract 005139 (INTERDEVO), and the European Young Investigator Award (EURYI) program (O.M.); from Spanish Government BFU2005-09378-C02-01 (L.P.); and from Nina Ireland and by National Institute of Mental Health Grants R01 MH49428 and K05 MH065670 (to J.L.R.R.). ; Peer reviewed

15 páginas, 7 figuras, 3 tablas. ; Terminal differentiation programs in the nervous system are encoded by cis-regulatory elements that control the expression of terminal features of individual neuron types. We decoded the regulatory information that controls the expression of five enzymes and transporters that define the terminal identity of all eight dopaminergic neurons in the nervous system of the Caenorhabditis elegans hermaphrodite. We show that the tightly coordinated, robust expression of these dopaminergic enzymes and transporters ("dopamine pathway") is ensured through a combinatorial cis-regulatory signature that is shared by all dopamine pathway genes. This signature is composed of an Ets domain-binding site, recognized by the previously described AST-1 Ets domain factor, and two distinct types of homeodomain-binding sites that act in a partially redundant manner. Through genetic screens, we identified the sole C. elegans Distalless/Dlx ortholog, ceh-43, as a factor that acts through one of the homeodomain sites to control both induction and maintenance of terminal dopaminergic fate. The second type of homeodomain site is a Pbx-type site, which is recognized in a partially redundant and neuron subtype-specific manner by two Pbx factors, ceh-20 and ceh-40, revealing novel roles of Pbx factors in the context of terminal neuron differentiation. Taken together, we revealed a specific regulatory signature and cognate, terminal selector-type transcription factors that define the entire dopaminergic nervous system of an animal. Dopaminergic neurons in the mouse olfactory bulb express a similar combinatorial transcription factor collective of Ets/Dlx/Pbx factors, suggesting deep phylogenetic conservation of dopaminergic regulatory programs. ; This work was funded by EMBO post-doctoral fellowships and Marie Curie Funds (to M.D. and N.F.), the New York Stem Cell Foundation Fellowships and the Spanish Government (SAF2011-26273) (to N.F), the NIH (R01NS039996-05; R01NS050266-03 to O.H.; R01GM30997 to M.C.; R01GM054510 to R.S.M.; and F32GM099160 to N.A.), and the Stavanger University Hospital (to M.D.). N.F is a NARSAD Young Investigator. O.H. is an Investigator of the Howard Hughes Medical Institute. ; Peer reviewed

PMID:17392456 ; The function of the nervous system depends on the precision of axon wiring during development. Previous studies have demonstrated that Slits, a family of secreted chemorepellent proteins, are crucial for the proper development of several major forebrain tracts. Mice deficient in Slit2 or, even more so, in both Slit1 and Slit2 have defects in multiple axonal pathways, including corticofugal, thalamocortical, and callosal connections. In the spinal cord, members of the Robo family of proteins help mediate the function of Slits, but the relative contribution of these receptors to the guidance of forebrain projections remains to be determined. In the present study, we addressed the function of Robo1 and Robo2 in the guidance of forebrain projections by analyzing Robo1-, Robo2-, and Robo1;Robo2-deficient mice. Mice deficient in Robo2 and, more dramatically, in both Robo1 and Robo2, display prominent axon guidance errors in the development of corticofugal, thalamocortical, and corticocortical callosal connections. Our results demonstrate that Robo1 and Robo2 mostly cooperate to mediate the function of Slit proteins in guiding the major forebrain projections. ; This work was supported by grants from Spanish Government (BFU2005-04773/BMC) and the European Young Investigator (EURYI) program (O.M.) and from Association pour la Recherche sur le Cancer (A.C.). ; Peer reviewed

14 páginas, 8 figuras, 1 tabla. Material suplementario accesible online. ; Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features. ; This work was funded by the National Institutes of Health [R01NS039996-05 and R01NS050266-03 to O.H.; R01NS076558 to D.A.C.-R.; and R01NS070644 to R.S.M.]; a March of Dimes Foundation Grant (to D.A.C.-R.); the Spanish Government [SAF2011-26273 to N.F.]; a Marie Curie Career Integration Grant (to N.F.); a VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.); and a European Research Council Starting Grant (to N.F.). N.F. is a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator. O.H. is an Investigator of the Howard Hughes Medical Institute. Deposited in PMC for release after 6 months. ; Peer reviewed

17 páginas, 6 figuras, 1 tabla. Material suplementario de este artículo online en: https://www.frontiersin.org/articles/10.3389/fcell.2021.770458/full#supplementary-material ; The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories. ; This work was supported by the CIDEGenT excellence research program of the Valencian government (CIDEGENT/2019/044) and by the Spanish Ministry of Science, Innovation and Universities (RTI 2018-100872-J-I00) as well as by the Young IBRO Regions Connecting Award to IDP and the ERC Consolidator Grant 101002203 to NF. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). ; Peer reviewed