title: Photoactivated adenylyl cyclase (PAC) reveals novel mechanisms underlying cAMP-dependent axonal morphogenesis.
abstract: Spatiotemporal regulation of axonal branching and elongation is essential in the development of refined neural circuits. cAMP is a key regulator of axonal growth; however, whether and how intracellular cAMP regulates axonal branching and elongation remain unclear, mainly because tools to spatiotemporally manipulate intracellular cAMP levels have been lacking. To overcome this issue, we utilized photoactivated adenylyl cyclase (PAC), which produces cAMP in response to blue-light exposure. In primary cultures of dentate granule cells transfected with PAC, short-term elevation of intracellular cAMP levels induced axonal branching but not elongation, whereas long-term cAMP elevation induced both axonal branching and elongation. The temporal dynamics of intracellular cAMP levels regulated axonal branching and elongation through the activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), respectively. Thus, using PAC, our study for the first time reveals that temporal cAMP dynamics could regulate axonal branching and elongation via different signaling pathways.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi Hamakita-ku, Hamamatsu, Shizuoka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Iseki
authors.affiliation: The Graduate School for the Creation of New Photonics Industries, 1955-1 Kurematsu-cho, Nishiku, Hamamatsu, Shizuoka, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuki
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Koyama
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D009024:Morphogenesis; D009474:Neurons / Q000378:metabolism; D051381:Rats
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases