Dscam1 establishes the columnar units through lineage-dependent repulsion between sister neurons in the fly brain (original) (raw)

Dscam2 mediates axonal tiling in the Drosophila visual system

Nature, 2007

Sensory processing centres in both the vertebrate and the invertebrate brain are often organized into reiterated columns, thus facilitating an internal topographic representation of the external world. Cells within each column are arranged in a stereotyped fashion and form precise patterns of synaptic connections within discrete layers. These connections are largely confined to a single column, thereby preserving the spatial information from the periphery. Other neurons integrate this information by connecting to multiple columns. Restricting axons to columns is conceptually similar to tiling. Axons and dendrites of neighbouring neurons of the same class use tiling to form complete, yet non-overlapping, receptive fields1-3. It is thought that, at the molecular level, cellsurface proteins mediate tiling through contact-dependent repulsive interactions1,2,4,5, but proteins serving this function have not yet been identified. Here we show that the immunoglobulin superfamily member Dscam2 restricts the connections formed by L1 lamina neurons to columns in the Drosophila visual system. Our data support a model in which Dscam2 homophilic interactions mediate repulsion between neurites of L1 cells in neighbouring columns. We propose that Dscam2 is a tiling receptor for L1 neurons. The Drosophila visual system is a modular structure6,7. The retina contains 750 simple eyes, each containing eight photoreceptor neurons or R cells (R1-R8). R cells project into the brain, where they make connections within two neuropils, the lamina and medulla. R1-R6 neurons target to the lamina, where they form synapses with lamina neurons (L1-L5). R7, R8 and L1-L5 form connections in single columns within layers in the medulla, and each column contains one axon of each of these cell types. As a consequence of this wiring pattern, each column processes motion (lamina neurons) and colour (R7 and R8) from a single point in space6. Although some progress has been made in understanding how neurons select different layers within each of the 750 columns6, the molecular mechanisms that restrict synaptic connections to a single column are not known. Dscam2 belongs to a conserved family of cell-surface proteins expressed in the nervous systems of many different organisms8-10. Down syndrome cell adhesion molecule (DSCAM) was originally identified as an open reading frame in a region of human chromosome 21 critical for Down's syndrome11. There are four Dscam genes in the fly genome (Dscam, and Dscam2-4). They encode type I transmembrane proteins that share about 30% sequence identity and have a common extracellular domain comprising ten

Jumeaux, a novel Drosophila winged-helix family protein, is required for generating asymmetric sibling neuronal cell fates

Development

The great majority of neurons in the Drosophila embryonic CNS are generated through two successive asymmetric cell divisions; neuroblasts (NBs) divide to produce another NB and a smaller ganglion mother cell (GMC); GMCs divide to generate two sibling neurons which can adopt distinct identities. During the division of the first born GMC from the NB4-2 lineage, GMC4-2a, Inscuteable (Insc) is localised to the apical cortex, Pon/Numb is localised to the basal cortex and two daughters with distinct identities, the RP2 motoneuron and its sibling RP2sib, are born. Resolution of distinct sibling neuronal fates requires correct apical localisation of Insc to facilitate the asymmetric localisation and preferential segregation of Pon/Numb to the basal daughter destined to become RP2. Here we report that jumeaux (jumu), which encodes a new member of the winged-helix family of transcription factors, is required to mediate the asymmetric localisation and segregation of Pon/Numb but is dispensable...

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system

Nature communications, 2014

Multipotent precursors are plastic cells that generate different, stable fates at the correct number, place and time, to allow tissue and organ formation. While fate determinants are known to trigger specific transcriptional programs, the molecular pathway driving the progression from multipotent precursors towards stable and specific identities remains poorly understood. Here we demonstrate that, in Drosophila neural precursors, the glial determinant glial cell missing (Gcm) acts as a 'time bomb' and triggers its own degradation once the glial programme is stably activated. This requires a sequence of transcriptional and posttranscriptional loops, whereby a Gcm target first affects the expression and then acetylation of the fate determinant, thus controlling Gcm levels and stability over time. Defective homeostasis between the loops alters the neuron:glia ratio and freezes cells in an intermediate glial/neuronal phenotype. In sum, we identify an efficient strategy triggerin...

Differential adhesion during development establishes individual neural stem cell niches and shapes adult behaviour in Drosophila

PLOS Biology

Neural stem cells (NSCs) reside in a defined cellular microenvironment, the niche, which supports the generation and integration of newborn neurons. The mechanisms building a sophisticated niche structure around NSCs and their functional relevance for neurogenesis are yet to be understood. In the Drosophila larval brain, the cortex glia (CG) encase individual NSC lineages in membranous chambers, organising the stem cell population and newborn neurons into a stereotypic structure. We first found that CG wrap around lineage-related cells regardless of their identity, showing that lineage information builds CG architecture. We then discovered that a mechanism of temporally controlled differential adhesion using conserved complexes supports the individual encasing of NSC lineages. An intralineage adhesion through homophilic Neuroglian interactions provides strong binding between cells of a same lineage, while a weaker interaction through Neurexin-IV and Wrapper exists between NSC lineag...

Hunchback is required for the specification of the early sublineage of neuroblast 7-3 in the Drosophila central nervous system

Development, 2002

The Drosophila ventral nerve cord (VNC) derives from neuroblasts (NBs), which mostly divide in a stem cell mode and give rise to defined NB lineages characterized by specific sets of sequentially generated neurons and/or glia cells. To understand how different cell types are generated within a NB lineage, we have focused on the NB7-3 lineage as a model system. This NB gives rise to four individually identifiable neurons and we show that these cells are generated from three different ganglion mother cells (GMCs). The finding that the transcription factor Hunchback (Hb) is expressed in the early sublineage of NB7-3, which consists of the early NB and the first GMC (GMC7-3a) and its progeny (EW1 and GW), prompted us to investigate its possible role in NB7-3 lineage development. Our analysis revealed that loss of hb results in a lack of the normally Hb-positive neurons, while the later-born neurons (designated as EW2 and EW3) are still present. However, overexpression of hb in the whole...

N-Cadherin Orchestrates Self-Organization of Neurons within a Columnar Unit in the Drosophila Medulla

The Journal of Neuroscience, 2019

Columnar structure is a basic unit of the brain, but the mechanism underlying its development remains largely unknown. The medulla, the largest ganglion of the Drosophila melanogaster visual center, provides a unique opportunity to reveal the mechanisms of 3D organization of the columns. In this study, using N-cadherin (Ncad) as a marker, we reveal the donut-like columnar structures along the 2D layer in the larval medulla that evolves to form three distinct layers in pupal development. Column formation is initiated by three core neurons, R8, R7, and Mi1, which establish distinct concentric domains within a column. We demonstrate that Ncad-dependent relative adhesiveness of the core columnar neurons regulates their relative location within a column along a 2D layer in the larval medulla according to the differential adhesion hypothesis. We also propose the presence of mutual interactions among the three layers during formation of the 3D structures of the medulla columns.

Dscam guides embryonic axons by Netrin-dependent and -independent functions

Development, 2008

Developing axons are attracted to the CNS midline by Netrin proteins and other as yet unidentified signals. Netrin signals are transduced in part by Frazzled (Fra)/DCC receptors. Genetic analysis in Drosophila indicates that additional unidentified receptors are needed to mediate the attractive response to Netrin. Analysis of Bolwig's Nerve reveals that Netrin mutants have a similar phenotype to Down Syndrome Cell Adhesion Molecule (Dscam) mutants. Netrin and Dscam mutants display dose sensitive interactions suggesting that Dscam could act as a Netrin receptor. We show using cell overlay assays that Netrin binds to fly and vertebrate Dscam, and that Dscam binds Netrin with the same affinity as DCC. At the CNS midline, we find that Dscam and its paralog Dscam3 act redundantly to promote midline crossing. Simultaneous genetic knockout of the two Dscams and the Netrin receptor fra produces a midline crossing defect that is stronger than the removal of Netrins, suggesting that Dscams also function in a pathway parallel to Netrins. Additionally, over-expression of Dscam in axons that do not normally cross the midline is able to induce ectopic midline crossing, consistent with an attractive receptor function. Our results support the model that Dscams function as attractive receptors for Netrin and also act in parallel to Frazzled/DCC. Furthermore, the results suggest that Dscams have the ability to respond to multiple ligands and act as receptors for an unidentified midline attractive cue. These functions in axon guidance have implications for the pathogenesis of Down Syndrome.

The organization and evolution of the Dipteran and Hymenopteran Down syndrome cell adhesion molecule (Dscam) genes

RNA, 2004

The Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam) gene encodes an axon guidance receptor and can generate 38,016 different isoforms via the alternative splicing of 95 variable exons. Dscam contains 10 immunoglobulin (Ig), six Fibronectin type III, a transmembrane (TM), and cytoplasmic domains. The different Dscam isoforms vary in the amino acid sequence of three of the Ig domains and the TM domain. Here, we have compared the organization of the Dscam gene from three members of the Drosophila subgenus (D. melanogaster , the mosquito Anopheles gambiae, and the honeybee Apis mellifera. Each of these organisms contains numerous alternative exons and can potentially synthesize tens of thousands of isoforms. Interestingly, most of the alternative exons in one species are more similar to one another than to the corresponding alternative exons in the other species. These observations provide strong evidence that many of the alternative exons have arisen by reiterative exon duplication and deletion events. In addition, these findings suggest that the expression of a large Dscam repertoire is more important for the development and function of the insect nervous system than the actual sequence of each isoform.