title: Type IV Collagen Controls the Axogenesis of Cerebellar Granule Cells by Regulating Basement Membrane Integrity in Zebrafish.
abstract: Granule cells (GCs) are the major glutamatergic neurons in the cerebellum, and GC axon formation is an initial step in establishing functional cerebellar circuits. In the zebrafish cerebellum, GCs can be classified into rostromedial and caudolateral groups, according to the locations of their somata in the corresponding cerebellar lobes. The axons of the GCs in the caudolateral lobes terminate on crest cells in the dorsal hindbrain, as well as forming en passant synapses with Purkinje cells in the cerebellum. In the zebrafish mutant shiomaneki, the caudolateral GCs extend aberrant axons. Positional cloning revealed that the shiomaneki (sio) gene locus encodes Col4a6, a subunit of type IV collagen, which, in a complex with Col4a5, is a basement membrane (BM) component. Both col4a5 and col4a6 mutants displayed similar abnormalities in the axogenesis of GCs and retinal ganglion cells (RGCs). Although type IV collagen is reported to control axon targeting by regulating the concentration gradient of an axonal guidance molecule Slit, Slit overexpression did not affect the GC axons. The structure of the BM surrounding the tectum and dorsal hindbrain was disorganized in the col4a5 and col4a6 mutants. Moreover, the abnormal axogenesis of the caudolateral GCs and the RGCs was coupled with aberrant BM structures in the type IV collagen mutants. The regrowth of GC axons after experimental ablation revealed that the original and newly formed axons displayed similar branching and extension abnormalities in the col4a6 mutants. These results collectively suggest that type IV collagen controls GC axon formation by regulating the integrity of the BM, which provides axons with the correct path to their targets.
authors.affiliation: Laboratory of Organogenesis and Organ Function, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Devision of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Ultrastructural Research Team, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.affiliation: Ultrastructural Research Team, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors.forename: Kisa
authors.initials: K
authors.lastname: Kakiguchi
authors.affiliation: Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Higashiyama
authors.affiliation: Laboratory of Organogenesis and Organ Function, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi, Japan; Devision of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Laboratory of Organogenesis and Organ Function, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi, Japan; Devision of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hibi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001485:Basement Membrane / Q000254:growth & development / Q000378:metabolism; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism*; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D024141:Collagen Type IV; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; C492287:slit1a protein, zebrafish