The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages

The locus elav (ella-vee) of Drosophila melanogaster, which is necessary for the proper development of the embryonic and adult nervous systems, has been characterized both genetically and molecularly. This locus has been shown to be transcribed exclusively within, and ubiquitously throughout, the developing nervous system during Hours 6 to 12 of embryogenesis. We present in situ RNA localization data which demonstrate that elav is expressed in the central nervous system as well as the peripheral nervous system of embryos, larvae, pupae, and adults. We also demonstrate that elav is not transcribed in embryonic or larval neuroblasts (the neuronal progenitor cells), or in at least one type of glial cell. These data provide evidence that the requirement for elav function is not limited to the 6- to 12-hr embryonic nervous system and the adult eye and developing optic lobe, but that its function is required for the development and continued maintenance of all neurons of the organism.     

Signaling in glial development: differentiation migration and axon guidance.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. During development, a variety of reciprocal signaling interactions between glia and neurons dictate all parts of nervous system development. Glia may provide attractive, repulsive, or contact-mediated cues to steer neuronal growth cones and ensure that neurons find their appropriate synaptic targets. In fact, both neurons and glia may act as migrational substrates for one another at different times during development. Also, the exchange of trophic signals between glia and neurons is essential for the proper bundling, fasciculation, and ensheathement of axons as well as the differentiation and survival of both cell types. The growing number of links between glial malfunction and human disease has generated great interest in glial biology. Because of its relative simplicity and the many molecular genetic tools available, Drosophila is an excellent model organism for studying glial development. This review will outline the roles of glia and their interactions with neurons in the embryonic nervous system of the fly.     

The zebrafish as a model for studying neuroblastoma

Neuroblastoma is a tumor arising in the peripheral sympathetic nervous system and is the most common cancer in childhood. Since most of the cellular and molecular mechanisms underlying neuroblastoma onset and progression remain unknown, the generation of new in vivo models might be appropriate to better dissect the peripheral sympathetic nervous system development in both physiological and disease states. This review is focused on the use of zebrafish as a suitable and innovative model to study neuroblastoma development. Here, we briefly summarize the current knowledge about zebrafish peripheral sympathetic nervous system formation, focusing on key genes and cellular pathways that play a crucial role in the differentiation of sympathetic neurons during embryonic development. In addition, we include examples of how genetic changes known to be associated with aggressive neuroblastoma can mimic this malignancy in zebrafish. Thus, we note the value of the zebrafish model in the field of neuroblastoma research, showing how it can improve our current knowledge about genes and biological pathways that contribute to malignant transformation and progression during embryonic life.     

Regeneration and maintenance of the planarian midline is regulated by a slit orthologue

Several families of evolutionarily conserved axon guidance cues orchestrate the precise wiring of the nervous system during embryonic development. The remarkable plasticity of freshwater planarians provides the opportunity to study these molecules in the context of neural regeneration and maintenance. Here we characterize a homologue of the Slit family of guidance cues from the planarian Schmidtea mediterranea. Smed-slit is expressed along the planarian midline, in both dorsal and ventral domains. RNA interference (RNAi) targeting Smed-slit results in the collapse of many newly regenerated tissues at the midline; these include the cephalic ganglia, ventral nerve cords, photoreceptors, and the posterior digestive system. Surprisingly, Smed-slit RNAi knockdown animals also develop morphologically distinguishable, ectopic neural structures near the midline in uninjured regions of intact and regenerating planarians. These results suggest that Smed-slit acts not only as a repulsive cue required for proper midline formation during regeneration but that it may also act to regulate the behavior of neural precursors at the midline in intact planarians.     

The CNS midline cells and spitz class genes are required for proper patterning of Drosophila ventral neuroectoderm.

The Drosophila embryonic central nervous system (CNS) develops from sets of neuroblasts (NBs) which segregate from the ventral neuroectoderm during early embryogenesis. It is not well established how each individual NB in the neuroectoderm acquires its characteristic identity along the dorsal-ventral axis. Since it is known that CNS midline cells and spitz class genes (pointed, rhomboid, single-minded, spitz and Star) are required for the proper patterning of ventral CNS and epidermis originated from the ventral neuroectoderm, this study was carried out to determine the functional roles of the CNS midline cells and spitz class genes in the fate determination of ventral NBs and formation of mature neurons and their axon pathways. Several molecular markers for the identified NBs, neurons, and axon pathways were employed to examine marker gene expression profile, cell lineage and axon pathway formation in the spitz class mutants. This analysis showed that the CNS midline cells specified by single-minded gene as well as spitz class genes are required for identity determination of a subset of ventral NBs and for formation of mature neurons and their axon pathways. This study suggests that the CNS midline cells and spitz class genes are necessary for proper patterning of the ventral neuroectoderm along the dorsal-ventral axis.     

Dscam mutation leads to hydrocephalus and decreased motor function

The nervous system is one of the most complicated organ systems in invertebrates and vertebrates. Down syndrome cell adhesion molecule (DSCAM) of the immunoglobulin (Ig) superfamily is expressed widely in the nervous system during embryonic development. Previous studies in Drosophila suggest that Dscam plays important roles in neural development including axon branching, dendritic tiling and cell spacing. However, the function of the mammalian DSCAM gene in the formation of the nervous system remains unclear. Here, we show that Dscam^del17 mutant mice exhibit severe hydrocephalus, decreased motor function and impaired motor learning ability. Our data indicate that the mammalian DSCAM gene is critical for the formation of the central nervous system.     

Roles of glia in the Drosophila nervous system

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. Various insects, primarily the fruit fly Drosophila melanogaster and the moth Manduca sexta, have provided useful models of glial function during development. The present review will outline evidence of glial contributions to embryonic, visual, olfactory and wing development. We will also outline evidence for non-developmental functions of insect glia including blood-brain-barrier formation, homeostatic functions and potential contributions to synaptic function. Where relevant, we will also point out similarities between the functions of insect glia and their vertebrate counterparts.     

To adhere or not to adhere

The modulation of cell adhesion is fundamental to the morphogenesis that accompanies proper embryonic development. Cadherins are a large family of calcium-dependent cell adhesion molecules whose spatial and temporal expression is critical to the formation of the neural crest, a unique, multipotent cell type that contributes to the patterning of the vertebrate body plan. Neural crest cells arise from the embryonic ectoderm through inductive interactions and reside in the dorsal aspect of the neural tube. These cells under go an epithelial-to-mesenchymal transition and migrate to precise destinations in the embryo, where they go on to differentiate into such diverse structures as melanocytes, elements of the peripheral nervous system, and the craniofacial skeleton. Distinct cadherins are expressed during the induction, migration and differentiation of the neural crest. With the advent of genomic sequencing, assembly and annotation for various model organisms, it has become possible to elucidate the molecular mechanisms underlying cadherin expression, and how these cadherins function, during neural crest development. This review explores the known roles of cadherins and details, where relevant, how different cadherins are regulated during the formation of the neural crest.     

Semaphorins: a new class of immunoregulatory molecules

The immune and nervous systems play distinct roles in maintaining physiological homeostasis. Recent data indicates that these systems influence one another and share many proteins and pathways that are essential for their normal function and development. Molecules originally shown to be critical for the development of proper immune responses have recently been found to function in the nervous system. Conversely, neuronal guidance cues can modulate immune functions. Although semaphorins were originally identified as axon guidance factors active during neuronal development, several recent studies have identified indispensable functions for these molecules in the immune system. This review provides an overview of the rapidly emerging functions of semaphorins and their receptors in the immune system.     

Patterns and functions of STAT activation during Drosophila embryogenesis

The JAK/STAT pathway mediates cytokine signaling in mammals and is involved in the function and development of the hematopoietic and immune systems. To investigate the biological functions of the JAK/STAT pathway during Drosophila development, we examined the tissue-specific localization of the tyrosine-phosphorylated, or activated form of Drosophila STAT, STAT92E. Here we show that during Drosophila embryonic development STAT92E activation is prominently detected in multiple tissues and in different developmental stages. These tissues include the tracheal pits, elongating intestinal tracks, and growing axons. We demonstrate that stat92E mutants are defective in tracheal formation, hindgut elongation, and nervous system development. Conversely, STAT92E overactivation caused premature development of the tracheal and nervous systems, and over-elongation of the hindgut. These results suggest that STAT activation is involved in proper differentiation and morphogenesis of multiple tissues during Drosophila embryogenesis.     

BRCA2 is required for neurogenesis and suppression of medulloblastoma

Defective DNA damage responses in the nervous system can result in neurodegeneration or tumorigenesis. Despite the importance of DNA damage signalling, the neural function of many critical DNA repair factors is unclear. BRCA2 is necessary for homologous recombination repair of DNA and the prevention of diseases including Fanconi Anemia and cancer. We determined the role of BRCA2 during brain development by inactivating murine Brca2 throughout neural tissues. In striking contrast to early embryonic lethality after germ-line inactivation, Brca2(LoxP/LoxP);Nestin-cre mice were viable. However, Brca2 loss profoundly affected neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arose from DNA damage as Brca2(LoxP/LoxP);Nestin-cre mice showed extensive gammaH2AX in neural tissue and p53 deficiency restored brain histology but lead to rapid formation of medulloblastoma brain tumors. In contrast, loss of the Atm kinase did not markedly attenuate apoptosis after Brca2 loss, but did partially restore cerebellar morphology, supporting a genomic surveillance function for ATM during neurogenesis. These data illustrate the importance of Brca2 during nervous system development and underscore the tissue-specific requirements for DNA repair factors.     

Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system

The formation of synaptic connections during the development of the nervous system requires the precise targeting of presynaptic and postsynaptic compartments. Furthermore, synapses are continually modified in the brain by experience. Recently, the ubiquitin proteasome system has emerged as a key regulator of synaptic development and function. The modification of proteins by ubiquitin, and in many cases their subsequent proteasomal degradation, has proven to be an important mechanism to control protein stability, activity and localization at synapses. Recent work has highlighted key questions of the UPS during the development and remodeling of synaptic connections in the nervous system.     

To adhere or not to adhere: The role of Cadherins in neural crest development

The modulation of cell adhesion is fundamental to the morphogenesis that accompanies proper embryonic development. Cadherins are a large family of calcium-dependent cell adhesion molecules whose spatial and temporal expression is critical to the formation of the neural crest, a unique, multipotent cell type that contributes to the patterning of the vertebrate body plan. Neural crest cells arise from the embryonic ectoderm through inductive interactions and reside in the dorsal aspect of the neural tube. These cells under go an epithelial-to-mesenchymal transition and migrate to precise destinations in the embryo, where they go on to differentiate into such diverse structures as melanocytes, elements of the peripheral nervous system and the craniofacial skeleton. Distinct cadherins are expressed during the induction, migration and differentiation of the neural crest. With the advent of genomic sequencing, assembly and annotation for various model organisms, it has become possible to elucidate the molecular mechanisms underlying cadherin expression, and how these cadherins function, during neural crest development. This review explores the known roles of cadherins and details, where relevant, how different cadherins are regulated during the formation of the neural crest.Key words: cadherins, neural crest, EMT, induction, migration, differentiation     

Wnt Signaling in Neuromuscular Junction Development

Wnt proteins are best known for their profound roles in cell patterning, because they are required for the embryonic development of all animal species studied to date. Besides regulating cell fate, Wnt proteins are gaining increasing recognition for their roles in nervous system development and function. New studies indicate that multiple positive and negative Wnt signaling pathways take place simultaneously during the formation of vertebrate and invertebrate neuromuscular junctions. Although some Wnts are essential for the formation of NMJs, others appear to play a more modulatory role as part of multiple signaling pathways. Here we review the most recent findings regarding the function of Wnts at the NMJ from both vertebrate and invertebrate model systems.Wnt proteins are evolutionarily conserved, secreted lipo-glycoproteins involved in a wide range of developmental processes in all metazoan organisms examined to date. In addition to governing many embryonic developmental processes, Wnt signaling is also involved in nervous system maintenance and function, and deregulation of Wnt signaling pathways occurs in many neurodegenerative and psychiatric diseases (De Ferrari and Inestrosa 2000; Caricasole et al. 2005; Okerlund and Cheyette 2011). The first link between Wnt signaling and synapse development was established by Salinas and colleagues in the vertebrate nervous system (Lucas and Salinas 1997; Hall et al. 2000) and by Budnik and colleagues at the invertebrate neuromuscular junction (NMJ) (Packard et al. 2002). Since then, Wnt signaling has emerged as an essential regulator of synaptic development and function in both central and peripheral synapses. Although important roles for Wnt signaling have become known from studies in both the central and peripheral nervous system, this article is concerned with the role of Wnts at the NMJ.     

Extracellular matrix-associated protein Sc1 is not essential for mouse development

Sc1 is an extracellular matrix-associated protein whose function is unknown. During early embryonic development, Sc1 is widely expressed, and from embryonic day 12 (E12), Sc1 is expressed primarily in the developing nervous system. This switch in Sc1 expression at E12 suggests an importance for nervous-system development. To gain insight into Sc1 function, we used gene targeting to inactivate mouse Sc1. The Sc1-null mice showed no obvious deficits in any organs. These mice were born at the expected ratios, were fertile, and had no obvious histological abnormalities, and their long-term survival did not differ from littermate controls. Therefore, the function of Sc1 during development is not critical or, in its absence, is subserved by another protein.