How to build a dendritic tree: Insights from somatosensory neurons in C. elegans

Abstract

Neurons, the basic building blocks of the nervous system, receive information from other neurons or from the environment through thin processes called dendrites. My work uses the simple nervous system of C. elegans and specifically a pair of somatosensory neurons (the PVD neurons) to study how their highly arborized dendritic endings are developed and maintained. The branching pattern of PVD is characterized by stereotypic and sequential orthogonal branch decisions where secondary, tertiary and quaternary branches form structures resembling candelabra along the primary dendrite. Work in our laboratory identified what we have named the Menorin pathway: the conserved adhesion molecules SAX-7/L 1 CAM and MNR-1 /Menorin act together from the skin of the animal through the DMA-1/LRR leucine rich transmembrane receptor in PVD to pattern dendritic arbors. This ligand-receptor interaction is enhanced by the presence of LECT2/Chondromodulin II, a chemokine secreted from the muscle. In addition to the genes described, kpc-1/Furin, a gene encoding a proprotein convertase homolog of the mammalian Furin, was identified in genetic screens as a previously unknown factor involved in PVD dendrite patterning.;During my thesis work, I focused on two aspects of PVD somatosensory development. First, I characterized the role of the proprotein convertase KPC-1/Furin and investigated its genetic relationship to the Menorin pathway. In a second project, I explored different molecular and cellular factors that are required for the development and maintenance of the PVD 1° dendritic branch.;KPC-1/Furin promotes dendritic branch extension and controls the number of lower and higher order branches in PVD dendritic arbors. This convertase is required cell-autonomously to stimulate branch extension and to ensure appropriate, non-overlapping distribution of sister dendrites in somatosensory neurons by negatively regulating the Menorin pathway. These findings uncovered a previously unnoticed role of the proprotein convertase family in the development of dendrites and axons and demand a more detailed analysis of the diversified members of this family in mammals, including their potential impact in the formation of circuits in the nervous system.;In my second project, I addressed the ability of axons to influence dendrite patterning and maintenance using activity-independent mechanisms. Axons have the ability to guide dendrites and maintain contacts using activity-dependent or activity-independent mechanisms. Activity independent dendritic patterning and maintenance by axons relies on both secreted signals and contact-dependent cues that guide dendritic processes and stabilize them after they reach their destination. While advances have been made on how neuronal activity shapes and preserves neuronal circuits, little is known about axon-derived, contact-dependent factors in dendrite patterning and maintenance. Here, I provide evidence of an axo-dendritic, contact-dependent but activity-independent interaction where an axonal process is used as a scaffold for the outgrowth and maintenance of a primary dendrite. Through a combination of laser-ablation and genetic experiments, I was able to demonstrate that PVD 1° dendritic branches require the physical presence of the ALA axons but do not depend on ALA synaptic activity. Disruptions in ALA axon position by loss of function of MIG-6/Papilin or the UNC-6/Netrin pathway produce primary dendrite guidance defects. ALA-PVD interactions require two functions of the cell adhesion molecule SAX-7/L1 CAM: First, expression of SAX-7/L1 CAM in ALA works with other members of the Menorin pathway to facilitate outgrowth of the primary branch on the ALA axon. Second, SAX-7/L1 CAM serves a post-developmental role to maintain fasciculation between the already formed PVD 1° dendrite and the ALA axon. This mechanism requires SAX-7 in both ALA and PVD processes but is independent of the function of other members in the Menorin pathway. These findings highlight an unprecedented dual role for a molecule in axon-dependent development and maintenance of dendritic structures. Loss of L1 CAM function in humans produce the Corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus (CRASH) syndrome, a group of conditions that affect the nervous system. Understanding SAX-7 functions in this context will help to give insights about L 1 CAM contributions in assembly and integrity of the nervous system and may help to explain neurological abnormalities present in CRASH syndrome pathology.