The Batten Disease Palmitoyl Protein Thioesterase 1 Gene Regulates Neural Specification and Axon Connectivity during Drosophila Embryonic Development

Palmitoyl Protein Thioesterase 1 (PPT1) is an essential lysosomal protein in the mammalian nervous system whereby defects result in a fatal pediatric disease called Infantile Neuronal Ceroids Lipofuscinosis (INCL). Flies bearing mutations in the Drosophila ortholog Ppt1 exhibit phenotypes similar to the human disease: accumulation of autofluorescence deposits and shortened adult lifespan. Since INCL patients die as young children, early developmental neural defects due to the loss of PPT1 are postulated but have yet to be elucidated. Here we show that Drosophila Ppt1 is required during embryonic neural development. Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord. Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections. These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation. Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila. These findings may be relevant for understanding the developmental origin of neural deficiencies in INCL

The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

During development, the growth of the animal body is accompanied by a concomitant elongation of the peripheral nerves, which requires the elongation of integrated nerve fibers and the axons projecting therein. Although this process is of fundamental importance to almost all organisms of the animal kingdom, very little is known about the mechanisms regulating this process. Here, we describe the identification and characterization of novel mutant alleles of GlcAT-P, the Drosophila ortholog of the mammalian glucuronyltransferase b3gat1. GlcAT-P mutants reveal shorter larval peripheral nerves and an elongated ventral nerve cord (VNC). We show that GlcAT-P is expressed in a subset of neurons in the central brain hemispheres, in some motoneurons of the ventral nerve cord as well as in central and peripheral nerve glia. We demonstrate that in GlcAT-P mutants the VNC is under tension of shorter peripheral nerves suggesting that the VNC elongates as a consequence of tension imparted by retarded peripheral nerve growth during larval development. We also provide evidence that for growth of peripheral nerve fibers GlcAT-P is critically required in hemocytes; however, glial cells are also important in this process. The glial specific repo gene acts as a modifier of GlcAT-P and loss or reduction of repo function in a GlcAT-P mutant background enhances VNC elongation. We propose a model in which hemocytes are required for aspects of glial cell biology which in turn affects the elongation of peripheral nerves during larval development. Our data also identifies GlcAT-P as a first candidate gene involved in growth of integrated peripheral nerves and therefore establishes Drosophila as an amenable in-vivo model system to study this process at the cellular and molecular level in more detail

Robustness under Functional Constraint: The Genetic Network for Temporal Expression in Drosophila Neurogenesis

Precise temporal coordination of gene expression is crucial for many developmental processes. One central question in developmental biology is how such coordinated expression patterns are robustly controlled. During embryonic development of the Drosophila central nervous system, neural stem cells called neuroblasts express a group of genes in a definite order, which leads to the diversity of cell types. We produced all possible regulatory networks of these genes and examined their expression dynamics numerically. From the analysis, we identified requisite regulations and predicted an unknown factor to reproduce known expression profiles caused by loss-of-function or overexpression of the genes in vivo, as well as in the wild type. Following this, we evaluated the stability of the actual Drosophila network for sequential expression. This network shows the highest robustness against parameter variations and gene expression fluctuations among the possible networks that reproduce the expression profiles. We propose a regulatory module composed of three types of regulations that is responsible for precise sequential expression. This study suggests that the Drosophila network for sequential expression has evolved to generate the robust temporal expression for neuronal specification

Filling the gap between identified neuroblasts and neurons in crustaceans adds new support for Tetraconata

The complex spatio-temporal patterns of development and anatomy of nervous systems play a key role in our understanding of arthropod evolution. However, the degree of resolution of neural processes is not always detailed enough to claim homology between arthropod groups. One example is neural precursors and their progeny in crustaceans and insects. Pioneer neurons of crustaceans and insects show some similarities that indicate homology. In contrast, the differentiation of insect and crustacean neuroblasts (NBs) shows profound differences and their homology is controversial. For Drosophila and grasshoppers, the complete lineage of several NBs up to formation of pioneer neurons is known. Apart from data on median NBs no comparable results exist for Crustacea. Accordingly, it is not clear where the crustacean pioneer neurons come from and whether there are NBs lateral to the midline homologous to those of insects. To fill this gap, individual NBs in the ventral neuroectoderm of the crustacean Orchestia cavimana were labelled in vivo with a fluorescent dye. A partial neuroblast map was established and for the first time lineages from individual NBs to identified pioneer neurons were established in a crustacean. Our data strongly suggest homology of NBs and their lineages, providing further evidence for a close insect–crustacean relationship

Aquaporins: Multiple roles in the central nervous system

Copyright © 2007 SAGE PublicationsAquaporins (AQPs) represent a diverse family of membrane proteins found in prokaryotes and eukaryotes. The primary aquaporins expressed in the mammalian brain are AQP1, which is densely packed in choroid plexus cells lining the ventricles, and AQP4, which is abundant in astrocytes and concentrated especially in the end-feet structures that surround capillaries throughout the brain and are present in glia limitans structures, notably in osmosensory areas such the supraoptic nucleus. Water movement in brain tissues is carefully regulated from the micro- to macroscopic levels, with aquaporins serving key roles as multifunctional elements of complex signaling assemblies. Intriguing possibilities suggest links for AQP1 in Alzheimer's disease, AQP4 as a target for therapy in brain edema, and a possible contribution of AQP9 in Parkinson's disease. For all the aquaporins, new contributions to physiological functions are likely to continue to be discovered with ongoing work in this rapidly expanding field of research.Andrea J. Yoo