Parallel Processing of Appetitive Short- and Long-Term Memories In Drosophila

SummaryIt is broadly accepted that long-term memory (LTM) is formed sequentially after learning and short-term memory (STM) formation, but the nature of the relationship between early and late memory traces remains heavily debated [1–5]. To shed light on this issue, we used an olfactory appetitive conditioning in Drosophila, wherein starved flies learned to associate an odor with the presence of sugar [6]. We took advantage of the fact that both STM and LTM are generated after a unique conditioning cycle [7, 8] to demonstrate that appetitive LTM is able to form independently of STM. More specifically, we show that (1) STM retrieval involves output from γ neurons of the mushroom body (MB), i.e., the olfactory memory center [9, 10], whereas LTM retrieval involves output from αβ MB neurons; (2) STM information is not transferred from γ neurons to αβ neurons for LTM formation; and (3) the adenylyl cyclase RUT, which is thought to operate as a coincidence detector between the olfactory stimulus and the sugar stimulus [11–14], is required independently in γ neurons to form appetitive STM and in αβ neurons to form LTM. Taken together, these results demonstrate that appetitive short- and long-term memories are formed and processed in parallel

Identification and characterization of polyhomeotic PREs and TREs

AbstractThe polyhomeotic (ph) gene is a member of the Polycomb group of genes (Pc-G), which are required for the maintenance of the spatial expression pattern of homeotic genes. In contrast to homeotic genes, ph is ubiquitously expressed and it is quantitatively regulated. ph is negatively regulated by the Pc-G genes, except Psc, and positively regulated by the antagonist trithorax group of genes (trx-G), suggesting that Pc-G and trx-G response elements (PREs and TREs) exist at the ph locus. In this study, we have functionally characterized PREs and TREs at the ph locus that function in transgenic constructs. We have identified a strong PRE and TRE in the ph proximal unit as well as a weak one in the ph distal unit. The PRE/TRE of both ph units appear atypical compared with the well-defined homeotic maintenance elements because the minimal ph proximal response element activity requires at least 2 kb of sequence and does not work at long range. We have used chromatin immunoprecipitation experiments on cultured cells and embryos to show that Pc-G proteins are located in restricted regions, close to the ph promoters that overlap functionally defined PRE/TREs. Our data suggest that ph PRE/TREs are cis-acting DNA elements that modulate rather than silence Pc-G- and trx-G-mediated regulation, enlarging the role of these two groups of genes in transcriptional regulation

HTT is a repressor of ABL activity required for APP induced axonal growth

ABL tyrosine kinase activity controls several aspects of development including axon patterning. Amyloid precursor protein (APP) is linked to Alzheimer's disease and previous work established that ABL is a downstream effector in an Appl, the Drosophila App ortholog, signaling pathway which modulates axon outgrowth in the mushroom bodies (MBs), the fly memory center. Here we show that Abl is required for the MB neuron axonal growth. Importantly, both Abl overexpression and lack of expression produce a similar phenotype in the MBs indicating the necessity of tightly regulating ABL activity. We find that the fly huntingtin protein (HTT), the homolog of the protein involved in Huntington's disease, behaves genetically as a repressor of ABL activity. Supporting this, FRET-based measurements of in vivo ABL activity in the MBs reveal a clear increase in its activity when HTT levels are reduced. Thus, in addition to its many other reported roles, HTT acts as a negative regulator of ABL activity, at least in the MBs, to maintain its appropriate physiological levels necessary for axon growth.

Rôle de HR39 récepteur nucléaire aux stéroïdes dans le développement des corps pédonculés et la mémoire de Drosophila melanogaster

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Caractérisation des éléments de réponse aux protéines des groupes "Polycomb" et "Trithorax" au sein du locus "polyhomeotic", et recherche de nouveaux gènes membres de ces deux groupes chez "Drosophila melanogaster"

La régulation transcriptionnelle d'environ 120 loci, dont les gènes homéotiques, dépend de deux groupes antagonistes de trans-régulateurs : les gènes du groupe trithorax (trxG) et du groupe Polycomb (PcG), qui maintiennent, respectivement, un état transcriptionnel actif et inactif des gènes cibles. Les produits de ces deux groupes agissent au niveau des gènes en induisant une structure d'ordre supérieur de la chromatine, qui permet l'héritage épigénétique de l'état transcriptionnel. polyhomeotic (ph), un membre du PcG, est lui-même régulé par le PcG et le trxG. Toutefois, ph est régulé quantitativement, contrairement aux gènes homéotiques dont le patron d'expression est maintenu qualitativement (on/off). Nous avons étudié les éléments de réponse aux protéines du PcG (P.R.E.) et trxG (T.R.E.) au sein du locus ph...The transcriptional regulation of about 120 loci, including homeotic genes, depends upon two antagonistic groups of trans-regulator: the trithorax group genes (trxG) and the Polycomb group genes (PcG) that maintain active and inactive transcriptional states respectively. PcG and trxG proteins act at target genes by inducing a higher order chromatin structure that allows the epigenetic inheritance of transcriptional states. polyhomeotic (ph) belongs to the PcG and is itself regulated by the PcG and trxG. However, ph is regulated in a quantitative way, in contrast to the qualitative (on/off) maintenance of homeotic genes transcriptional expression pattern. We have studied Polycomb and trithorax groups response elements (PREs and TREs) at the ph locus. We identified two PREs/TREs : a strong ph proximal one that contains the main proximal endogenous regulatory elements, as well as another weaker ph distal one...ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Le développement des corps pédonculés chez Drosophila Melanogaster : Rôle des protéines tyrosine kinases SRC64 et linotte dans la croissance et le guidage des axones

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Gain-of-function screen identifies a role of the Src64 oncogene in Drosophila mushroom body development

International audienceMushroom bodies (MB) are substructures in the Drosophila brain that are essential for memory. At present, MB anatomy is rather well described when compared to other brain areas, and elucidation of the genetic control of the development and projection patterns of MB neurons will be important to the understanding of their functions. We have performed a gain-of-function screen in order to identify genes that are involved in MB development. We drove expression of genes in MB neurons by crossing 2407 GAL4-driven UY element lines to lines containing an MB GAL4 source and UAS-GFP elements, and looked for defects in the MB structure. We have molecularly identified the genomic regions adjacent to the 26 positive UY insertions and found 18 potential genes that exhibit adult MB gain-of-function phenotypes. The proteins encoded by these candidate genes include, as well as genes with yet unknown function, transcription factors (e.g., tramtrack), nanos RNA-binding protein, microtubule-severing protein, vesicle trafficking proteins, axon guidance receptor, and the Src64 cytoplasmic protein tyrosine kinase. These genes are involved in key features of neuron cell biology. In three cases, tramtrack, nanos, and Src64, we show that the open reading frame located directly downstream of the UY P element is indeed the expressed target gene. Loss-of-function mutations of both ttk and Src64 lead to MB phenotypes proving that these genes are involved in the genetic control of MB development. Moreover, Src64 is shown here to act in a cell-autonomous fashion and is likely to interact with the previously-identified linotte/derailed receptor tyrosine kinase in MB development

Genome Wide Prediction of Polycomb/Trithorax Response Elements in Drosophila melanogaster

Ringrose L, Rehmsmeier M, Dura J-M, Paro R. Genome Wide Prediction of Polycomb/Trithorax Response Elements in Drosophila melanogaster. Developmental Cell. 2003;5:759-771

The Leucine Zipper Motif of the Drosophila AF10 Homologue Can Inhibit PRE-Mediated Repression: Implications for Leukemogenic Activity of Human MLL-AF10 Fusions

In a screen for Drosophila genes that interfere with transcriptional repression mediated by the Polycomb group of genes, we identified a dominant mutation affecting the Alhambra (Alh) gene, the fly homologue of the human AF10 gene. AF10 has been identified as a fusion partner of both MLL and CALM in infant leukemias. Both fusion proteins retain the leucine zipper domain of AF10 but not its PHD domain. We show here that, while the full-length ALH protein has no activity on Polycomb group-responsive elements (PREs), overexpression of the isolated ALH leucine zipper domain activates several PREs. Within the ALH full-length protein, the PHD domain inhibits the PRE deregulation mediated by the leucine zipper domain. This deregulation is conserved in the human AF10 leucine zipper domain, which confers the same activity on an oncogenic MLL-AF10 fusion protein expressed in Drosophila melanogaster. These data reveal new properties for the leucine zipper domain and thus might provide new clues to understanding the mechanisms by which AF10 fusion proteins in which the PHD domain is lost might trigger leukemias in humans