Analysis and Digital Reconstruction of Drosophila Brain Development
Digital 3D models play an increasingly important role in neuroscience. Representing three-dimensional scaffolds in which functional and gene expression data are entered and displayed graphically, the digital models become analytical tools that allow one to address neural connectivity and function, as well as gene function and gene interactions.
We are generating standardized digital atlas models of the developing Drosophila brain, a system used by many to investigate the genetic mechanism controlling the formation and function of neuronal circuits. Our studies on brain development have always put a strong emphasis on the lineage because it can be considered as a genetic and structural unit. Lineages with their tracts, and the compartments formed by their arbors, provide an anatomical and developmental framework to which all neurons can be referred. We reason that (some) lineages of the Drosophila brain can serve as a paradigm to connect gene expression to brain function/behavior: Developmentally, neurons of a lineage share a certain genetic program (transcription factors expressed by the neuroblast); structurally, they assemble into a compartment with specific circuit properties and function.
Lineages and compartments that are visible from the late embryo towards the adult. Compartments along with lineages and their tracts form a stereotyped pattern that are captured in digital models. The goal of this modeling project is to provide a tool shared with the community, allowing one to exploit the Drosphila brain more efficiently for developmental-genetic and functional questions.
Group Members: Amelia Younossi-Hartenstein, Jennifer Lovick, Jaison Omoto
Characterization of Glial Cell Development in the Drosophila Central Nervous System
Glia represent a major cellular constituent of invertebrate and vertebrate nervous systems. Although glial cells were originally thought to be simple "space filling" support cells for the more studied neurons, accumulating evidence suggests an active role for glia in nearly every aspect of proper nervous system development, function, and maintenance. However, many fundamental aspects of glial cell biology remain poorly understood. Recently, several molecularly and morphologically distinct glial subtypes have been identified in Drosophila. These heterogeneous glial subtypes appear to fulfill evolutionarily conserved functions akin to vertebrate glial subtypes. Thus, Drosophila, being amenable to powerful genetic and molecular manipulation, is an excellent model system to gain fundamental insight into glial cell biology.
We aim to describe the basic development of glial cell subtypes in the Drosophila brain. A thorough description of glial cell subtype proliferation, migration, and morphology will lay the foundation for a more systematic characterization of mechanisms governing glial cell development and function in the future. We are concurrently conducting an RNAi-based reverse genetics screen using glia-specific GAL4 drivers to identify genes which regulate these aspects of glial cell biology.
Group member: Jaison Omoto
Development of the Drosophila optic lobe
The visual system in both vertebrates and invertebrates require a precise topographic map, with the correct neuronal subtype specified in a tightly regulated spatiotemporal fashion. We are interested in using the fly optic lobe to model the vertebrate retina.
Our first aim is to elucidate the signaling mechanisms that regulate all stages of retina development: from the proliferation of progenitor cells and initial cell fate specification to proper synapse targeting and layer formation. We and others have identified Jak-Stat, Notch, EGFR, and Hippo pathways to be important for regulating the molecular switch from symmetric to asymmetrically dividing cells. We are trying to further understand how extracellular signals can ultimately affect cell fate decisions in the medulla.
Secondly, we hypothesize that like the vertebrate model,the time of birth can specify a given retinal cell type. Recent work by the Sato group has shown that four transcription factors specify the birth of medulla neurons (Hth, Drf, Run, and Bsh). To test our hypothesis on the temporal requirement of neuronal birth order, we will birthdate different retinal subtypes that make up a single module in the optic lobe, the so-called 'column' by making single-cell FRT clones by MARCM. If both of these hypotheses turn out to be correct, that is, if cell fate is ultimately controlled by local cell-to-cell interactions (from first aim), this will represent a highly useful fly model which resembles the vertebrate nervous system much more than the strictly intrinsically specified lineages that make up the central brain.
Group Member: Kathy Ngo
Stem Cells and endocrine cells in the Drosophila intestine
The developing Drosophila intestine has yielded insight into the interaction between self renewing stem cells and their microenvironment (stem cell niches); furthermore, it is one of the few invertebrate models where the formation of the entero-endocrine system can be studied. We have followed the emergence of these intestinal cell types from the embryo to the adult. We are currently investigating the molecular mechanisms of endocrine cell specification, focusing on the gene tap, a homolog of the mammalian Neurogenin 3.
Group Members: Amelia Younossi-Hartenstein
Hartenstein V., "From blood to brain: the neurogenic niche of the crayfish brain", Dev Cell 30: 253-254 (2014).
Kuert PA, Hartenstein V, Bello BC, Lovick JK, Reichert H., "Neuroblast lineage identification and lineage-specific Hox gene action during postembryonic development of the subesophageal ganglion in the Drosophila central brain", Dev Biol 390: 102-115 (2014).
Hammonds AS, Bristow CA, Fisher WW, Weiszmann R, Wu S, Hartenstein V, Kellis M, Yu B, Frise E, Celniker SE., "Spatial expression of transcription factors in Drosophila embryonic organ development", Genome Biol 14: (2014).
Ito K, Shinomiya K, Ito M, Armstrong JD, Boyan G, Hartenstein V, Harzsch S, Heisenberg M, Homberg U, Jenett A, Keshishian H, Restifo LL, R÷ssler W, Simpson JH, Strausfeld NJ, Strauss R, Vosshall LB; Insect Brain Name Working Group., "A systematic nomenclature for the insect brain", Neuron 81: 755-765 (2014).
Hartenstein V, Jacobs D., "Developmental plasticity, straight from the worm's mouth", Cell 155: 742-743 (2013).
Wong DC, Lovick JK, Ngo KT, Borisuthirattana W, Omoto JJ, Hartenstein V., "Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones", Dev Biol 384: 258-289 (2013).
Lovick JK, Ngo KT, Omoto JJ, Wong DC, Nguyen JD, Hartenstein V., "Postembryonic lineages of the Drosophila brain: I. Development of the lineage-associated fiber tracts", Dev Biol 384: 228-257 (2013).
Gross GG, Lone GM, Leung LK, Hartenstein V, Guo M., "X11/Mint genes control polarized localization of axonal membrane proteins in vivo", J Neurosci 33: 8575-8586 (2013).
Hartenstein V, Wodarz A, "Initial neurogenesis in Drosophila", Wiley Interdiscip Rev Dev Biol 2: 701-721 (2013).
Takashima S, Paul M, Aghajanian P, Younossi-Hartenstein A, Hartenstein V., "Migration of Drosophila intestinal stem cells across organ boundaries", Development 140: 1903-1911 (2013).
Grigorian M, Hartenstein V., "Hematopoiesis and hematopoietic organs in arthropods", Dev Genes Evol 223: 103-115 (2013).
Hartenstein V., "Stem cells in the context of evolution and development", Dev Genes Evol 223: 1-3 (2013).
Takashima S, Gold D, Hartenstein V., "Stem cells and lineages of the intestine: a developmental and evolutionary perspective", Dev Genes Evol 223: 85-102 (2013).
Das A, Gupta T, Davla S, Prieto-Godino LL, Diegelmann S, Reddy OV, Raghavan KV,
Reichert H, Lovick J, Hartenstein V, "Neuroblast lineage-specific origin of the neurons of the Drosophila larval olfactory system", Dev Biol 373: 322-337 (2013).
Bailly X, Reichert H, Hartenstein V, "The urbilaterian brain revisited: novel insights into old questions from new flatworm clades. Bailly X, Reichert H, Hartenstein V", Dev Genes Evol 223: 149-157 (2013).