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ABSTRACT The Netrin receptor Dcc and its Drosophila homolog Frazzled play crucial roles in diverse developmental process, including axon guidance. In Drosophila, Fra regulates midline axon guidance through a Netrin-dependent and a Netrin-independent pathway. However, what molecules regulate these distinct signaling pathways remain unclear. To identify Fra-interacting proteins, we performed affinity purification mass spectrometry to establish a neuronal-specific Fra interactome. In addition to known interactors of Fra and Dcc, including Netrin and Robo1, our screen identified 85 candidate proteins, the majority of which are conserved in humans. Many of these proteins are expressed in the ventral nerve cord, and gene ontology, pathway analysis and biochemical validation identified several previously unreported pathways, including the receptor tyrosine phosphatase Lar, subunits of the COP9 signalosome and Rho-5, a regulator of the metalloprotease Tace. Finally, genetic analysis demonstrates that these genes regulate axon guidance and may define as yet unknown signaling mechanisms for Fra and its vertebrate homolog Dcc. Thus, the Fra interactome represents a resource to guide future functional studies.
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Diverse roles for axon guidance pathways in adult tissue architecture and function
Abstract Classical axon guidance ligands and their neuronal receptors were first identified due to their fundamental roles in regulating connectivity in the developing nervous system. Since their initial discovery, it has become clear that these signaling molecules play important roles in the development of a broad array of tissue and organ systems across phylogeny. In addition to these diverse developmental roles, there is a growing appreciation that guidance signaling pathways have important functions in adult organisms, including the regulation of tissue integrity and homeostasis. These roles in adult organisms include both tissue‐intrinsic activities of guidance molecules, as well as systemic effects on tissue maintenance and function mediated by the nervous and vascular systems. While many of these adult functions depend on mechanisms that mirror developmental activities, such as regulating adhesion and cell motility, there are also examples of adult roles that may reflect signaling activities that are distinct from known developmental mechanisms, including the contributions of guidance signaling pathways to lineage commitment in the intestinal epithelium and bone remodeling in vertebrates. In this review, we highlight studies of guidance receptors and their ligands in adult tissues outside of the nervous system, focusing on in vivo experimental contexts. Together, these studies lay the groundwork for future investigation into the conserved and tissue‐specific mechanisms of guidance receptor signaling in adult tissues. Key PointsAxon guidance ligand and receptor expression often persist into adulthood in neuronal and non‐neuronal tissues alike.Recent work in genetic model organisms highlights the diverse roles of guidance factors in adult tissues.Guidance factors are required intrinsically in a variety of adult tissues but can also regulate tissue function indirectly via functions in the nervous and vascular systems.Studies outside of the nervous system are likely to enhance our understanding of these diverse siganling molecules and could suggest novel signaling modalities in the nervous system.
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- Award ID(s):
- 1853719
- PAR ID:
- 10372955
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Natural Sciences
- Volume:
- 2
- Issue:
- 4
- ISSN:
- 2698-6248
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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