BNIP-H Recruits the Cholinergic Machinery to Neurite Terminals to Promote Acetylcholine Signaling and Neuritogenesis

• Published in: Developmental cell 2015-09, Vol.34 (5), p.555-568
• Main Authors: Sun, Jichao, Pan, Catherine Qiurong, Chew, Ti Weng, Liang, Fengyi, Burmeister, Margit, Low, Boon Chuan
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Animals; Cell Line; Choline O-Acetyltransferase - metabolism; Cholinergic Agents - pharmacology; Nerve Tissue Proteins - metabolism; Neurites - metabolism; Neurons - metabolism; Rats; Signal Transduction - physiology; Synaptic Transmission - physiology
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2015.08.006

Synthesis and release of neurotransmitters such as acetylcholine (ACh) are key to synaptic function. However, little is known about the spatial regulation of their synthesizing machinery. Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. There, BNIP-H/ACL complex synergistically recruits another enzyme choline acetyltransferase (ChAT), leading to enhanced secretion of ACh. ACh then activates MAPK/ERK via muscarinic receptors to promote neurite outgrowth. In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth. Significantly, Bnip-h knockdown in zebrafish causes developmental defect in motor neurons through impaired cholinergic pathway, leading to motor disorder. Therefore, precise targeting of the cholinergic machinery through BNIP-H is essential for the local production of ACh for morphogenesis and neurotransmission. •BNIP-H acts as a scaffold to link and transport ACL on kinesin-1 toward neurite ends•BNIP-H and ACL recruit ChAT at neurite ends to increase ACh level for neuritogenesis•Human Cayman ataxia splice mutant impairs trafficking of ACL and neurite outgrowth•Bnip-h depletion disrupts zebrafish ACh signal, motor neuron development, and mobility How the cholinergic machinery is spatially regulated within neurons is not fully understood. Sun et al. now show that the ataxia-related protein BNIP-H/Caytaxin facilitates kinesin-dependent transport of ATP citrate lyase, an enzyme required for acetylcholine synthesis, to neurite terminals, thus supporting neurite outgrowth and, in zebrafish, motor neuron development.