Molecular basis of nervous system development and function in Drosophila
The major interests of our lab are to understand the molecular control of neural circuit assembly, maintenance, and function.
Assembly and function of somatosensory circuitry
Somatosensory representation in the central nervous system is poorly understood. We are working to uncover how somatosensory circuits are organized and how connection specificity is established. An anatomical map at single axon resolution of somatosensory projections within the CNS revealed precise differences in axon targeting among distinct groups of sensory neurons. We are now taking molecular, anatomical, and behavioral approaches to identify interneurons in the CNS that are targets of somatosensory neurons. With this information we aim to define the organization and behavioral relevance of interneuron cell types, as well as to determine how sensory axons and interneurons establish their specific connections.
Dendritic territory formation
Dendritic arbors fill characteristic territories, and these territories determine where and how they receive sensory or synaptic input. Dendrite-dendrite repulsion mechanisms establish field sizes in both vertebrate and invertebrate. We are interested in the cellular and molecular mechanisms of dendritic repulsion between cells of the same type (called tiling) and repulsion between sister branches from the same neuron (termed self-avoidance. We have shown that Down syndrome cell adhesion molecule (Dscam) is a key component of dendrite self-avoidance machinery. Normally sister dendrites do not cross each other. However, when individual neurons are made mutant for Dscam, their arbors cross extensively. By alternative splicing Dscam generates over 38,000 distinct isoforms (just over 19,000 distinct ectodomains, each of which is potentially capable of homophilic binding). Isoform diversity is dispensable for self-avoidance. However, overexpression of individual Dscam isoforms in dendrites that normally overlap leads to segregation of their territories. Thus, Dscam diversity permits self vs. non-self discrimination in neurons. This capacity for self-avoidance depends critically on integrin receptors , which control the three-dimensional positioning of arbors and ensure that dendrites contact each other as they grow.
A current focus of the lab is to understand the molecular underpinning of dendritic tiling, a related phenomenon in which arbors from different cells avoid crossing. A tiling mode of organization is observed widely in many different cell types, but the molecular basis for tiling is not known. Thus we hope that these studies can reveal general patterning mechanisms.
Mechanisms of nervous system structural and functional maintenance during aging
How do neurons and circuits change at the molecular, structural, and functional levels as an animal ages? We are exploring this problem and identifying molecules that help to maintain structural and functional integrity of neurons during aging.
- Bouchard M.B., Voleti V., Mendes C.S., Grueber W.B., Mann R.S., Bruno R.M., Hillman E.M.C (2015) Swept confocally-aligned planar excitation (SCAPE) microscopy for high-speed volumetric imaging of behaving organisms. Nature Photonics 9:113-119.link
- Singhania, A, Grueber W.B. (2014) Development of the embryonic and larval peripheral nervous system of Drosophila. WIREs Developmental Biology 3:193-210.
- Ziegenfuss J.S., Grueber W.B. (2013) SAX-7 and Menorin light the path for dendrite morphogenesis. Cell 155:269-271.
- Grueber W.B. (2013) Dendrite Development: Invertebrates, In: J.L.R. Rubenstein and P. Rakic editors: Comprehensive Developmental Neuroscience: Cellular Migration and Formation of Neuronal Connections, Amsterdam: Academic Press, pp. 191-212.
- Zipursky S.L., Grueber W.B. (2013) The molecular basis of self-avoidance. Ann Rev Neurosci. 26:547-568. PubMed
- Hoang P., Grueber W.B. (2013) Dendritic self-avoidance: protocadherins have it covered. Cell Res. 23:323-325. Full Text
- Kim M.E., Shrestha B.R., Blazeski R., Mason C.A., Grueber W.B. (2012) Integrins establish dendrite-substrate relationships that promote dendritic self-avoidance and patterning inDrosophila sensory neurons. Neuron 73:79-91. PubMed
- Matthews B.J., Grueber W.B. (2011) Dscam1-mediated self-avoidance counters netrin-dependent targeting of dendrites in Drosophila. Curr Biol 21:1480-1487. PubMed Full Text
- Shrestha B.R., Grueber W.B. (2011) Methods for exploring the genetic control of sensory dendrite morphogenesis in Drosophila. Cold Spring Harb Protoc 2011(8):910-916. PubMed
- Shrestha B.R., Grueber W.B. (2011) Analysis of dendrite development in Drosophila embryos. Cold Spring Harb Protoc. 2011(8): 967-972. PubMed
- Shrestha B.R., Grueber W.B. (2011) Generation and staining of MARCM clones in Drosophila. Cold Spring Harb Protoc. 2011(8): 973-979. PubMed
- Shrestha B.R., Grueber W.B. (2010) Neuronal morphogenesis: Worms get an EFF in dendritic arborization. Curr Biol. 20:R673-R675. PubMed
- Grueber W.B., Sagasti A. (2010) Self-avoidance and Tiling: Mechanisms of Dendrite and Axon Spacing. Cold Spring Harb Perspect Biol doi:10.1101/cshperspect.a001750. PubMed
- Hattori D., Chen Y., Matthews B.J., Salwinski L., Sabatti C., Grueber W.B., Zipursky S.L. (2009) Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature 461:644-648. PubMed
- Zlatic M., Li F., Strigini M., Grueber W., Bate M. (2009). Positional Cues in the Drosophila Nerve Cord: Semaphorins Pattern the Dorso-Ventral Axis. PLoS Biol 7(6): e1000135. doi:10.1371/journal.pbio.1000135 PubMed
- Corty M.M., Matthews B.J., Grueber W.B. (2009). Molecules and mechanisms of dendrite development in Drosophila. Development 136:1049-1061. PubMed Free text
- Matthews B.J., Corty M.M., Grueber W.B. (2008). Of cartridges and columns: New roles for cadherins in visual system development. Neuron 58:1-3. PubMed
- Matthews B.J., Kim M.E.*, Flanagan J.J.*, Hattori D., Clemens J.C., Zipursky S.L., Grueber W.B. (2007). Dendrite self-avoidance is controlled by Dscam. Cell 129:593-604. PubMed