
Jonathan Benito-SiposAutonomous University of Madrid | UAM · Department of Biology
Jonathan Benito-Sipos
PhD
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Publications (61)
The central nervous system contains a daunting number of different cell types. Understanding how each cell acquires its fate remains a major challenge for neurobiology. The developing embryonic ventral nerve cord (VNC) of Drosophila melanogaster has been a powerful model system for unraveling the basic principles of cell fate specification. This pe...
A striking feature of the nervous system pertains to the appearance of different neural cell sub‐types at different axial levels. Studies in the Drosophila central nervous system reveals that one mechanism underlying such segmental differences pertains to the segment‐specific removal of cells by programmed cell death (PCD). One group of genes invol...
The MCM2-7 complex is a highly conserved hetero-hexameric protein complex, critical for DNA unwinding at the replicative fork during DNA replication. Overexpression or mutation in MCM2-7 genes is linked to and may drive several cancer types in humans. In mice, mutations in MCM2-7 genes result in growth retardation and mortality. All six MCM2-7 gene...
The Drosophila embryonic central nervous system (CNS) is a powerful model system for addressing basic mechanisms of nervous system development. Studies during the last three decades have resulted in a detailed description of the basic anatomical features of the CNS, as well as an in-depth understanding of the molecular genetic mechanisms acting to...
During embryonic development, a number of genetic cues act to generate neuronal diversity. While intrinsic transcriptional cascades are well-known to control neuronal sub-type cell fate, the target cells can also provide critical input to specific neuronal cell fates. Such signals, denoted retrograde signals, are known to provide critical survival...
Significant splicing events in brr2 mutants (|ΔΨ| >0,03; q<0.25).
Values relative to the splicing events associated with the respective gene region (FlyBase gene symbol), using the Benjamini-Hochberg procedure. ES (Exon skipping), A5SS (Alternative 5' splice sites), A3SS (Alternative 3' splice sites), ME (Mutually exclusive exons), IR (Intron reten...
Differential alternative splicing (DAS) analysis data of Prp8 mutants.
Numerical data related to DAS analysis. Event_id: contains the gene cluster, chromosome, strand, position, gene ID, and exon path information. Event_type: ES (Exon skipping), A5SS (Alternative 5' splice sites), A3SS (Alternative 3' splice sites), ME (Mutually exclusive exons), I...
Related to Fig 4. Ectopic expression of the BMP ligand Gbb in brr2 mutants.
(A-B) Ap cluster neurons (white arrows), identified by ap-Gal4>UAS-GFP, immunostained for FMRFa and Nplp1, in control and in brr2 mutants ectopically expressing gbb (ap>gbb;brr2). Transgenic expression of gbb does not result in rescue of FMRFa expression.
(EPS)
Related to Fig 6. Prp8 phenocopies brr2 mutants.
(A-F) Confocal, 2–5 layer projection images of the Ap cluster showing expression pattern of the late factors in the specification cascade by immunostaining of Eyes absent (Eya), Dimmed (Dimm) and phosphorylated form of Mothers against dpp (pMad) in Prp8 mutants (Prp804p024; E-F) compared to the patte...
Related to Fig 5. Tv4 neuron axonal pathfinding in control.
3D reconstruction video from confocal images showing the axonal pathfinding of the Ap cluster (ap> RFP, red) and the Tv4 neurons (FMRFa>GFP, green) in the thoracic segment T3 of control flies at stage AFT. The reconstruction shows Tv4 projection to the midline and then dorsal, establishing...
Significant splicing events common to brr2 and Prp8 mutants (|ΔΨ| >0,03; q<0.25).
Values relative to the splicing events associated with the respective gene region (FlyBase gene symbol), using the Benjamini-Hochberg procedure. ES (Exon skipping), A5SS (Alternative 5' splice sites), A3SS (Alternative 3' splice sites), ME (Mutually exclusive exons),...
Expression levels and splicing events detected for genes with the “TGF-β receptor signaling pathway” GO identifier in brr2 mutants.
Values relative to the gene (FlyBase gene symbol) expression levels expressed as fold change, and splicing events for genes with the “TGF-β receptor signaling pathway” GO identifier in brr2 mutants. Expression in CNS i...
Spreadsheet form of numerical data and summary statistics.
Numerical data related to graphs and summary statistics in the Figs 1, 3, 5, S1, S4 and S5.
(XLSX)
Related to Fig 6. Top Gene Ontology terms affected in brr2 mutants (b).
(A) Gene Ontology (GO) enrichment analysis of genes showing both splicing events and 2-fold transcription changes in brr2 mutants (GeneCodis). (B) Venn diagram showing axon guidance affected genes in brr2 mutants.
(EPS)
Related to Fig 4. Dorsal neurohemal organ inervation by apterous cluster neurons in control.
3D reconstruction video from confocal images showing the axonal pathfinding of Ap cluster neurons (ap>GFP, green) innervating the dorsal neurohemal organ (DHN, buttonless-lacZ, blue) in the thoracic segments T2-T3 of control flies at stage AFT.
(MP4)
Related to Fig 5. Tv4 neuron axonal pathfinding in brr2 mutants with rescued FMRFa expression.
3D reconstruction video from confocal images showing the axonal pathfinding of the Ap cluster (ap> RFP, red) in brr2 mutants rescued by transgenic expression of activated BMP receptors (saxA and tkvA). Expression of FMRFa-eGFP reporter make possible to id...
Significant splicing events in Prp8 mutants (|ΔΨ| >0,03; q<0.25).
Values relative to the splicing events associated with the respective gene region (FlyBase gene symbol), using the Benjamini-Hochberg procedure. ES (Exon skipping), A5SS (Alternative 5' splice sites), A3SS (Alternative 3' splice sites), ME (Mutually exclusive exons), IR (Intron reten...
Differential alternative splicing (DAS) analysis data of brr2 mutants.
Numerical data related to DAS analysis. Event_id: contains the gene cluster, chromosome, strand, position, gene ID, and exon path information. Event_type: ES (Exon skipping), A5SS (Alternative 5' splice sites), A3SS (Alternative 3' splice sites), ME (Mutually exclusive exons), I...
Gene expression levels 2-fold up- or down-regulated in brr2 mutants.
Values relative to the gene (FlyBase gene symbol) expression levels with 2-fold change in brr2, expressed as RPKM (Reads Per Kilobase per Million). The table also shows a comparison of the expression levels detected for those same genes in Prp8 mutants. brr2 and Prp8 fold change i...
Expression levels and splicing events detected for genes with the “axon guidance” GO identifier affected in brr2 mutants.
Values relative to the gene (FlyBase gene symbol) expression levels expressed as fold change, and splicing events for genes with the “axon guidance” GO identifier affected in brr2 mutants. ES (Exon skipping), A5SS (Alternative 5...
Ilp7 expression is not affected in brr2 mutants.
(A-D) Expression of Ilp7, Dimm, pMad and FMRFa-GFP reporter, in control and brr2 (brr209c117). Ilp7 expression not affected in Ilp7 neurons (dashed lines) in brr2 mutants. Identification, using Dimm, of the previously described four Ilp7 expressing neurons (C-D dashed lines), which are BMP signaling...
Related to Fig 6. Top Gene Ontology terms affected in brr2 mutants.
(A) Gene Ontology (GO) enrichment analysis of genes showing splicing events in brr2 mutants (GeneCodis). (B) Gene Ontology (GO) enrichment analysis of genes showing 2-fold transcription changes in brr2 mutants (GeneCodis).
(EPS)
Related to Fig 3. Expression of PMad in thoracic and abdominal segments of VNC in brr2 mutants.
(A-F) Expression of pMad in control (A, D) and brr2 mutant (B,E) thoracic segments of stage AFT embryos. Eya (in thorax) and Dimm (in abdomen) immunostaining was used to identify neuropeptide expressing cells and provide a reference for delimiting the se...
Related to Fig 5. Characterization of FMRFa rescue.
(A-C) Expression of FMRFa>GFP (FMRFa), ap>RFP and pMad, in ap-Gal4;brr2 mutants (brr209c117) transgenically expressing saxA and tkvA, at AFT. pMad expression is rescued in the Ap cluster by ectopic expression of active forms of Tkv and Sax, although FMRFa expression is not restored in every segmen...
Related to Fig 4. Dorsal neurohemal organ innervation failure by apterous cluster neurons in brr2 mutants.
3D reconstruction video from confocal images showing the axonal pathfinding of Ap cluster neurons (ap>GFP, green) and the absence of innervation to the dorsal neurohemal organ (DHN, buttonless-lacZ, blue) in the thoracic segments T2-T3 of brr2...
In this study, we identify the means by which segmentally homologous neurons acquire different neuropeptide fates in Drosophila. Ventral abdominal (Va)-neurons in the A1 segment of the ventral nerve cord express DH31 and AstA neuropeptides (neuropeptidergic fate I) by virtue of Ubx activity, whereas the A2-A4 Va-neurons express the Capa neuropeptid...
Gain-of-function experiments using the elav-Gal4 driver.
Expression of Dimm (green) and DH31 (red) in elav>Ubx (A), elav>abdA (B) and elav>Antp (C). (D) Quantitation of genetic studies [n ≥8 VNC in all genotypes; asterisks indicate significant difference compared with control (Student’s t-test, P<0.001)]. Genotypes: (A) elav-Gal4/UAS-Ubx, (B) elav-...
Scr (Sex combs reduced) immunoreactivity did not expand posteriorly.
Expression of Dimm (green) and Scr (red) in wild type and Antennapedia mutants. Genotypes: (A) AntpNS-rvc12/Antp14 and (B) OregonR.
(PDF)
Va-A1 neurons survive into larval stages.
Expression of Dimm (green) and Dac (red) in wild type at larval stage III. Genotype: OregonR.
(PDF)
AbdA levels are unaffected in by cas-Gal4>UAS-Antp overexpression.
(A, B) Expression of Capa (green) and AbdA (red) in controls (A) and cas>Antp (B). (C) Quantitation of genetic studies [n ≥8 VNC]. Genotypes: (A) OregonR, (B) cas-Gal4/UAS-Antp
(PDF)
During Drosophila embryonic nervous system development, neuroblasts express a programmed cascade of five temporal transcription factors that govern the identity of cells generated at different time-points. However, these five temporal genes fall short of accounting for the many distinct cell types generated in large lineages. Here, we find that the...
Specification of the myriad of unique neuronal subtypes found in the nervous system depends upon spatiotemporal cues and terminal selector gene cascades, often acting in sequential combinatorial codes to determine final cell fate. However, a specific neuronal cell subtype can often be generated in different parts of the nervous system and at differ...
Data underlying Figs 3L, 3N, 4G, 5, 6E, 6F and S5D.
(XLSX)
lbe acts in parallel with Antp, cas, and hth.
(A–F) GFP/βgal, Col, Nab, and Lbe expression in the NB5-6T at St14 in control and Antp, cas, and hth mutants. Antp and hth mutants show loss of Col expression, while Lbe expression is not affected. (D) cas mutants show, in addition to a negative Col expression, a loss of Nab expression, since cas regula...
Grn expression in the NB5-6 lineage at two different stages.
(A) Co-staining for βgal of the grn-lacZ and Eya to analyze the expression of grn-lacZ at the Ap cluster at St16. We do not find grn-lacZ expression in the NB5-6 lineage at St 16. (B) Co-staining for GFP of the lbe(K)-GFP (to visualize the NB5-6 lineage) together with βgal for the grn-lac...
Origin of supernumerary Eya cells in col and lbe co-misexpression.
(A, B) Co-staining for βgal, Dimm, Eya, and GsbN of the mirror-lacZ construct in (A) control and (B) elav-Gal4>UAS-col, UAS-lbe genetic background. White dotted lines represent the Gsbn compartment whereas magenta dotted lines represent the Mirr compartment. Supernumerary Eya cells...
Kr, pdm, and grn are not required for dAp cell survival.
(A–C) Co-staining for Dimm and Eya in Kr, pdm, and grn mutants, in which cell death has been impaired by Df(3R)H99 or by expression of cell death blocker UAS-p35. dAp cells are lost in mutants and not restored by cell death impairment.
(TIF)
Origin of extra dAp cells in hb mutant background.
Co-staining for GFP and Eya of the col-dAp-GFP enhancer (to visualize the NB4-3 from which dAp cell originated) in (A) control and (B) hb mutant background. Both the bonafide dAp and the supernumerary one are GFP positive. Thus, the supernumerary dAp generated in hb mutant originate from the NB4-3....
Castor is not expressed in the NB4-3 early lineage and dAp is generated in a type I division mode.
(A and B) Co-staining for GFP and Cas of the col-dAp-GFP enhancer (to visualize the NB4-3 lineage from which dAp cell originated) at Stage 12 and 13 to analyze the expression of Cas in the NB4-3 lineage when it is generating the dAp neuron. Cas is not...
Overexpression of grn.
(A-C) Co-staining for Eya, Nplp1 and Col in (A) control, (B) pros-Gal4>UAS-grn, and (C) elav-Gal4>UAS-grn genetic background. Overexpression of grn is not able to induce ectopic dAp neurons. (D) Quantification of Nplp1 and Eya expressing dAp cells in control, prospero-Gal4>UAS-grn, and elav-Gal4>UAS-grn genetic background VNC...
Studies in the Drosophila embryonic NB4-2 lineage have suggested that the transcription factor Klumpfuss (Klu) functions within embryonic neuroblast lineages to differentiate between the identities of two adjacent ganglion mother cells (GMCs). However, because of the limited lineage markers available, these observations have been made only for the...
A number of transcription factors that are expressed within most, if not all, embryonic neuroblast (NB) lineages participate in neural subtype specification. Some have been extensively studied in several NB lineages (e.g. components of the temporal gene cascade) whereas others only within specific NB lineages. To what extent they function in other...
Drosophila embryonic neuroblasts generate different cell types at different time points. This is controlled by a temporal cascade of Hb→Kr→Pdm→Cas→Grh, which acts to dictate distinct competence windows sequentially. In addition, Seven up (Svp), a member of the nuclear hormone receptor family, acts early in the temporal cascade, to ensure the transi...
The central nervous system contains a wide variety of neuronal subclasses generated by neural progenitors. The achievement of a unique neural fate is the consequence of a sequence of early and increasingly restricted regulatory events, which culminates in the expression of a specific genetic combinatorial code that confers individual characteristic...
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología. Fecha de lectura: 16-02-2007
Identification of the genetic mechanisms underlying the specification of large numbers of different neuronal cell fates from limited numbers of progenitor cells is at the forefront of developmental neurobiology. In Drosophila, the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial cues....
It is becoming increasingly clear that the activation of specific terminal differentiation genes during neural development is critically dependent upon the establishment of unique combinatorial transcription factor codes within distinct neural cell subtypes. However, it is still unclear to which extent these codes are shared by lineage-unrelated ne...
The distribution of leucokinin (LK) neurons in the central nervous system (CNS) of Drosophila melanogaster was described by immunolabelling many years ago. However, no detailed underlying information of the input or output connections of their neurites was then available. Here, we provide a more accurate morphological description by employing a nov...
One of the most widely studied phenomena in the establishment of neuronal identity is the determination of neurosecretory phenotype, in which cell-type-specific combinatorial codes direct distinct neurotransmitter or neuropeptide selection. However, neuronal types from divergent lineages may adopt the same neurosecretory phenotype, and it is unclea...
Prospero is required in dividing longitudinal glia (LG) during axon guidance; initially to enable glial division in response to neuronal contact, and subsequently to maintain glial precursors in a quiescent state with mitotic potential. Only Prospero-positive LG respond to neuronal ablation by over-proliferating, mimicking a glial-repair response....
A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal deg...