title: Regulation of ECM degradation and axon guidance by growth cone invadosomes.
abstract: Invadopodia and podosomes, collectively referred to as invadosomes, are F-actin-rich basal protrusions of cells that provide sites of attachment to and degradation of the extracellular matrix. Invadosomes promote the invasion of cells, ranging from metastatic cancer cells to immune cells, into tissue. Here, we show that neuronal growth cones form protrusions that share molecular, structural and functional characteristics of invadosomes. Growth cones from all neuron types and species examined, including a variety of human neurons, form invadosomes both in vitro and in vivo. Growth cone invadosomes contain dynamic F-actin and several actin regulatory proteins, as well as Tks5 and matrix metalloproteinases, which locally degrade the matrix. When viewed using three-dimensional super-resolution microscopy, F-actin foci often extended together with microtubules within orthogonal protrusions emanating from the growth cone central domain. Finally, inhibiting the function of Tks5 both reduced matrix degradation in vitro and disrupted motoneuron axons from exiting the spinal cord and extending into the periphery. Taken together, our results suggest that growth cones use invadosomes to target protease activity during axon guidance through tissues.
authors.affiliation: Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Santiago-Medina
authors.affiliation: Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Gregus
authors.affiliation: Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Nichol
authors.affiliation: Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: O'Toole
authors.affiliation: Department of Neuroscience and Neuroscience Training Program, University of Wisconsin, Madison, WI 53706, USA tmgomez@wisc.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Gomez
mesh_terms: D000199:Actins / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000502:physiology*; D022081:Cell Surface Extensions / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D020439:Growth Cones / Q000502:physiology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D015151:Immunoblotting; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014982:Xenopus laevis
chemical_list: D000199:Actins; D033942:Adaptor Proteins, Vesicular Transport; C478582:SH3PXD2A protein, human; D020782:Matrix Metalloproteinases
keywords: Axon guidance; Neural development; Pathfinding; Xenopus