Cell surface codes for olfactory circuit assembly
- Weizhe Hong.
- May 2012.
- Physical description
- online resource (xii, 86 pages) : illustrations (some color)
- Hong, Weizhe.
- Clandinin, Thomas R. (Thomas Robert), 1970- thesis advisor.
- Luo, Liqun, 1966- thesis advisor (primary).
- Nelson, W. J. (W. James) thesis advisor.
- Shen, Kang, 1972- thesis advisor.
- Stanford University. Department of Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 79-86).
- Neurons are interconnected with extraordinary precision to allow proper propagation and integration of neural activities. The organization of these specific connections emerges from sequential developmental events, including axon guidance, target selection, and synapse formation. Compared to axon guidance, little is known about how selection and matching between pre- and post-synaptic partners are achieved. To ensure the proper relay of olfactory information in flies, axons of ~50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ~50 classes of projection neurons (PNs). Previous developmental analysis has shown that PN dendrites first target to specific areas within the developing antennal lobe to create a proto-map. This is followed by ORN axon invasion into the antennal lobe. However, it is unclear (1) how PNs target their dendrites to specific areas and (2) how ORN axons subsequently recognize PN dendrites to form highly specific one-to-one connections. To address the first question, I conducted a genetic screen to identify new genes involved in PN dendrite targeting. I identified Capricious, a leucine-rich repeat transmembrane protein that is differentially expressed in different PN classes. Loss- and gain-of-function studies indicate that Capricious instructs the segregation of Capricious-positive and negative PN dendrites to discrete glomerular targets. Moreover, the function of Capricious in regulating PN dendrite targeting is independent of pre-synaptic ORNs. The closely related protein Tartan plays a partially redundant function with Capricious. Therefore, these leucine-rich repeat proteins instruct targeting of PN dendrites to discrete glomeruli in the antennal lobe. To address the second question, we designed highly sensitive and robust assays to examine the matching and mismatching between PNs and ORNs. This allowed me to perform two unbiased screens, which independently identified two Teneurins, Ten-m and Ten-a, as synaptic matching molecules. Teneurins are EGF repeat-containing transmembrane proteins that are evolutionarily conserved from worms to mammals. Drosophila Teneurins, Ten-m and Ten-a, are highly expressed in select PN and ORN matching pairs. Loss- and gain-of-function of Teneurins cause specific mismatching of ORN axons and PN dendrites. Moreover, Teneurins promote homophilic interactions in vitro, and homophilically mediate trans-cellular interactions to promote PN-ORN attraction in vivo. Therefore, I propose that Teneurins instruct synaptic matching specificity between PNs and ORNs through homophilic attraction. The identification of Teneurins reveals a general mechanism for determining synapse specificity directly between pre- and post-synaptic neurons. In summary, I have identified two major mechanisms for the stepwise assembly of the olfactory circuit. In the first step, PN dendrites target to specific, discrete glomerular locations in the antennal lobe through a pair of leucine-rich repeat transmembrane proteins, Capricious and Tartan. Subsequently, ORN axons arrive at the antennal lobe, and recognize PN dendrites through homophilic attractions mediated by a pair of EGF repeat-containing transmembrane proteins, Ten-m and Ten-a. These molecules and underlying mechanisms not only help mechanistically understand the olfactory circuit assembly but also elucidate the general principles by which wiring specificity is established.
- Drosophila Proteins > metabolism
- Drosophila melanogaster > cytology
- Drosophila melanogaster > metabolism
- Olfactory Pathways > physiology
- Receptors, Cell Surface > metabolism
- Olfactory Receptor Neurons > metabolism
- Synapses > metabolism
- Publication date
- Submitted to the Department of Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2012.