Multiple parallel cell lineages in the developing mammalian cerebral cortex

Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not in mouse. Neurons followed parallel differentiation trajectories in the gyrus and sulcus, with different expressions of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex.This work was supported by ERC-AdG grant Neurocentro-885382 to M.G. and by Spanish State Research Agency grants SAF2015-69168-R, PGC2018-102172-B, and PDI2021-125618NB and “Severo Ochoa” Programme for Centers of Excellence in R&D (CEX-2021-00165-S) to V.B. Additional support was provided by Spanish State Research Agency FPI contract (BES-2016-077737) to L.D.-V.-A., “JdC incorporación” fellowship (IJC2020-044653-I) to V.F., and by Fundación Tatiana Pérez de Guzmán el Bueno fellowship to A.P.-C.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX-2021-00165-S).Peer reviewe

Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier

B-cell chronic lymphoproliferative disorders (B-CLPD) encompass a group of hematologic tumors that often present with leukemic involvement.1 Their heterogeneity and the lack of relatively specific diagnostic markers for most of these diseases make their diagnosis challenging, especially in cases that only have blood involvement or when histology is not available. With the currently used immunophenotypic and molecular markers, around 10% of B-CLPD cases remain unclassifiable and are categorized as B-CLPD, not otherwise specified (B-CLPD, NOS)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Zic2 regulates the expression of Sert to modulate eye-specific refinement at the visual targets

The development of the nervous system is a time-ordered and multi-stepped process that requires neural specification, axonal navigation and arbor refinement at the target tissues. Previous studies have demonstrated that the transcription factor Zic2 is necessary and sufficient for the specification of retinal ganglion cells (RGCs) that project ipsilaterally at the optic chiasm midline. Here, we report that, in addition, Zic2 controls the refinement of eye-specific inputs in the visual targets by regulating directly the expression of the serotonin transporter (Sert), which is involved in the modulation of activity-dependent mechanisms during the wiring of sensory circuits. In agreement with these findings, RGCs that express Zic2 ectopically show defects in axonal refinement at the visual targets and respond to pharmacological blockage of Sert, whereas Zic2-negative contralateral RGCs do not. These results link, at the molecular level, early events in neural differentiation with late activity-dependent processes and propose a mechanism for the establishment of eye-specific domains at the visual targets.Research in the laboratory of EH is funded by grants from the Spanish Ministry of Science and Innovation (BFU2007-61831), CONSOLIDER-Ingenio Program (CDS2007-023) and a CDA from the Human Frontiers Science Program.Peer Reviewe

Genetics and development of the optic chiasm

In animals with binocular vision, retinal fibers either project across the midline or they remain on the same side of the ventral diencephalon, forming an X-shaped commissure known as the optic chiasm. The correct formation of the optic chiasm during development is essential to establish a fully functional visual system. Visual dysfunction associated with axonal misrouting at the optic chiasm has been described in albino individuals and in patients with non-decussating retinal-fugal fiber syndrome. Although little is known about the causes of retinal misrouting in these conditions, the molecular mechanisms responsible for the formation of the optic chiasm are beginning to be elucidated in vertebrates. This review focuses on our current knowledge of how the optic chiasm forms, which will hopefully help us to better understand these congenital anomalies.Peer Reviewe

Unidad de vectores neurotrópicos

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

Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms

Axons of retinal ganglion cells (RGCs) make a divergent choice at the optic chiasm to cross or avoid the midline in order to project to ipsilateral and contralateral targets, thereby establishing the binocular visual pathway. The zinc-finger transcription factor Zic2 and a member of the Eph family of receptor tyrosine kinases, EphB1, are both essential for proper development of the ipsilateral projection at the mammalian optic chiasm midline. Here, we demonstrate in mouse by functional experiments in vivo that Zic2 is not only required but is also sufficient to change the trajectory of RGC axons from crossed to uncrossed. In addition, our results reveal that this transcription factor regulates the expression of EphB1 in RGCs and also suggest the existence of an additional EphB1-independent pathway controlled by Zic2 that contributes to retinal axon divergence at the midline.Research in the laboratory of E.H. is funded by grants from the Spanish Ministry of Education and Science (BFU2004-558, BFU2007-61831), CONSOLIDER-Ingenio 2010 Program (CDS2007-023), the Regional Government of ‘Generalitat Valenciana’, and a CDA from the Human Frontiers Science Program. Research in the laboratory of C.M. is funded by R01 EY12736 and EY01529 grants from the NIH.Peer Reviewe

Callosal inputs generate side-invariant receptive fields in the barrel cortex [Dataset]

The study was supported by MINECO [PGC2018-094457-B-I00] and CSIC-Severo Ochoa Excellence Programmes of the Instituto de Neurociencias [SEV-2013-0317 and SEV-2017-0723]. R.M. is supported by la Caixa-Severo Ochoa programme [2016/00006/001]; A.A-A. is supported by the ACIF-GVA programme; J.A-C is supported by the CSIC-Severo Ochoa Excellence Programme of the Instituto de Neurociencias [SEV2013-0317].Peer reviewe

Slit/Robo Signaling Modulates the Proliferation of Central Nervous System Progenitors

Neurogenesis relies on a delicate balance between progenitor maintenance and neuronal production. Progenitors divide symmetrically to increase the pool of dividing cells. Subsequently, they divide asymmetrically to self-renew and produce new neurons or, in some brain regions, intermediate progenitor cells (IPCs). Here we report that central nervous system progenitors express Robo1 and Robo2, receptors for Slit proteins that regulate axon guidance, and that absence of these receptors or their ligands leads to loss of ventricular mitoses. Conversely, production of IPCs is enhanced in Robo1/2 and Slit1/2 mutants, suggesting that Slit/Robo signaling modulates the transition between primary and intermediate progenitors. Unexpectedly, these defects do not lead to transient overproduction of neurons, probably because supernumerary IPCs fail to detach from the ventricular lining and cycle very slowly. At the molecular level, the role of Slit/Robo in progenitor cells involves transcriptional activation of the Notch effector Hes1. These findings demonstrate that Robo signaling modulates progenitor cell dynamics in the developing brain. Video Abstract: Borrell et al. demonstrate that Slit-Robo signaling regulates the progression from radial glia to intermediate progenitor cells in the embryonic mouse cerebral cortex. Robo effects are mediated by regulation of Hes1 transcription independently of, and synergistically to, Notch. © 2012 Elsevier Inc.Supported by grants from Spanish Ministry of Economy and Innovation MINECO (SAF2011-28845 and CONSOLIDER CSD2007-00023) to O.M. R01 NIH(NINDS) to L.M., and MINECO (SAF2009-07367) and the International Human Frontier Science Program Organization to V.B. A.C. and G.C. are recipients of a >Formacion de Personal Investigador> (FPI) fellowship from the MINECO.Peer Reviewe