Role of DE-Cadherin in Neuroblast Proliferation, Neural Morphogenesis, and Axon Tract Formation inDrosophilaLarval Brain Development

Abstract

In the wild-type brain, the Drosophila classic cadherin DE-cadherin is expressed globally by postembryonic neuroblasts and their lineages ("secondary lineages"), as well as glial cells. To address the role of DE-cadherin in the larval brain, we took advantage of the dominant-negative DE-cad(ex) construct, the expression of which was directed to neurons, glial cells, or both. Global expression of DE-cad(ex) driven by a heat pulse during the early second instar resulted in a severe phenotype that included deficits in neural proliferation. Neuroblasts appeared in approximately normal numbers but had highly reduced mitotic activity. When the DE-cad(ex) construct was driven by the glial-specific driver gcm-Gal4, the effect of DE-cad(ex) on neuroblast proliferation could be replicated, which indicates that DE-cadherin acts in glial cells to promote proliferation of neuroblasts. Expression of DE-cad(ex) in neurons, cortex glia, or both results in abnormalities in cortex layering and in trajectories of secondary axons. In the wild-type brain, neuroblasts and neurons generated at different time points are arranged concentrically around the neuropile, with the DE-cadherin-positive neuroblasts and young secondary neurons at the surface, followed by older secondary neurons and primary neurons. Axons of secondary lineages follow a straight radial course toward the neuropile. Processes of glial cells located in the cortex form a scaffold, called trophospongium, that enwraps neuroblasts and neurons. Expression of DE-cad(ex) in neurons, cortex glia, or both disrupted the regular placement of neuroblasts and secondary neurons and resulted in abnormal trajectories of cell body fiber tracts. We conclude that DE-cadherin plays a pivotal role in larval brain proliferation, brain cortex morphogenesis, and axon growth.

Cell migration inDrosophilaoptic lobe neurons is controlled byeyeless/Pax6

“…1F,G) (Dumstrei et al, 2003). Dumstrei et al (Dumstrei et al, 2003) showed that global expression of a dominant-negative form of DE-Cadherin driven by a heat pulse during early second instar results in a severe phenotype that includes deficits in neural proliferation: although neuroblasts appears in approximately normal numbers, they have highly reduced mitotic activity.…”

“…Loss of ey function causes overproliferation of neuroblasts and prevents dispersion, leading to large clusters of eypositive neurons. Formation of these large clusters can be rescued by removal of DE-Cadherin (Shotgun -FlyBase), which regulates cell adhesion and neuroblast proliferation (Dumstrei et al, 2003). Thus, eyeless links neurogenesis and migration in the optic lobe, revealing new mechanisms of brain formation in Drosophila that are similar to cortical development in mammals (Ge et al, 2006).…”

Insights into neural stem cell biology from flies

“…DE-cadherin expression is significantly lower in grh mutant neuroblasts, and Grh-binding sites have been identified in the DE-cadherin flanking sequences (Almeida & Bray 2005). It is thought that DE-cadherin mediates neuroblast-glia interactions that are required for proper neuroblast proliferation (Dumstrei et al 2003). The elucidation of further Grh targets and how these targets might vary in a segment-specific way to control the different behaviours of thoracic and abdominal neuroblasts will be of great interest.…”

Drosophila asymmetric division, polarity and cancer

“…Drosophila GSCs fulfil this definition because they are totally dependent on direct contact with a niche of specialized cells to the extent that GSCs that abandon their niche lose SC identity and differentiating daughter cells that establish ectopic contact with the niche might acquire SC identity (Brawley and Matunis, 2004;Kai and Spradling, 2004). Indeed, NBs occupy defined anatomical positions during development and are in close contact with neighbouring cells: their most recent daughters on the basal side (Truman and Bate, 1988), and cortex glial cells on their apical and lateral sides (Dumstrei et al, 2003). Moreover, NBs are not insensitive to their neighbours and are definitively responsive to signals like Anachronism or Activin, which are secreted by larval glia (Ebens et al, 1993;Zhu et al, 2008) as well as to Notch, and other signalling pathways that control the number of proliferating NBs in the larval brain (Park et al, 2003;Wang et al, 2006;Lee et al, 2006a).…”