title: Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling.
abstract: Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMNs) as a model system. SACMNs are a homogeneous population of spinal MNs with axons that leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein BEN. We show that the homeodomain transcription factor Nkx2.9 is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMNs and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Bravo-Ambrosio
authors.forename: Grant
authors.initials: G
authors.lastname: Mastick
authors.forename: Zaven
authors.initials: Z
authors.lastname: Kaprielian
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D014157:Transcription Factors; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C112924:Nkx2-9 protein, mouse; C498888:Robo2 protein, mouse; C120010:Slit1 protein, mouse