November 21, 2014

Monday Night Neuroscience Seminars – Frank Polleux, Columbia – “Role of LKB1-dependent Signaling in Axon Morphogenesis and Presynaptic Function in vivo”

Date/Time
Date(s) - 07/28/2014
8:00 pm - 9:00 pm
Location
Speck Auditorium

Monday Night Neuroscience Seminars
Frank Polleux, Columbia
“Role of LKB1-dependent Signaling in Axon Morphogenesis and Presynaptic Function in vivo
Speck Auditorium, 8:00 PM

ABSTRACT:

The molecular mechanisms underlying axon morphogenesis and circuit formation in the developing mammalian central nervous system are still poorly understood. Our lab identified the polarity kinase LKB1 (STK11, Par4) as a key regulator of axon morphogenesis: LKB1 is required and sufficient for axon formation during early stages of neuronal polarization in vivo (Barnes et al., 2007) and for terminal axon branching at later stages of development (Courchet, Lewis et al. 2013). LKB1 is a ‘master’ kinase activating 14 other downstream kinases defining an entire branch of the kinome, the AMPK family of serine/threonine kinases. We demonstrated that LKB1 regulates axon formation/specification through activation of two related kinases (SAD-A/B a.k.a. BRSK1/2) but regulates terminal axon branching through activation of NUAK1 (a.k.a. ARK5), a poorly characterized downstream target of LKB1. We discovered that this novel LKB1-NUAK1 kinase pathway promotes the capture of mitochondria specifically at nascent presynaptic sites (Courchet, Lewis et al. 2013) and we used molecular effectors of mitochondria immobilization in the axon (such as syntaphilin) to demonstrate the causal relationship between presynaptic mitochondria capture and axon branching (Courchet, Lewis et al. 2013).

These results define new functions for LKB1-dependent kinases during axon morphogenesis through regulation of mitochondria dynamics but also raise two important and largely unexplored questions: (1) what are the molecular mechanism underlying stable capture of mitochondria at presynaptic release sites in developing axons? And (2) how do presynaptic mitochondria regulate axon branching? I will present some preliminary results suggesting that mitochondria-ER interaction might be involved in presynaptic mitochondria capture and that presynaptic mitochondria are critical for regulating neurotransmitter release properties through regulation of presynaptic calcium clearance.