Role of motoneuron-derived neurotrophin 3 in survival and axonal projection of sensory neurons during neural circuit formation

Abstract

SUMMARYSensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.

Discovery of new glomerular disease–relevant genes by translational profiling of podocytes in vivo

“…Among the downregulated genes were neurotrophin-3 (Ntf3, a.k.a. nerve growth factor 2), which has been reported to promote survival and axonal projection of sensory neurons (22), angiotensin I converting enzyme 2 (Ace2), which has been shown to be expressed in podocytes (23) and to attenuate diabetic nephropathy when overexpressed in podocytes (24), angiotensinogen (Agt), angiopoietin 2 (Angpt2), the serine proteinase inhibitor Serpina 6, and the matrix components fibronectin 1 (Fn1) and collagen, type IV, alpha 1 (Col4a1). Among the upregulated genes were tropomodulin-2 (Tmod2, a.k.a.…”

Blocking Apoptotic Signaling Rescues Axon Guidance in Netrin Mutants

“…Classically, the axonal target tissue produces neurotrophic factors. An increasing number of examples are now known where intermediate targets supply neurotrophic factors, a phenomenon termed en passant or pretarget neurotrophic action (Wang and Tessier-Lavigne, 1999; Usui et al, 2012; Kuruvilla et al, 2004; Furne et al, 2008). Because NetB is expressed by the CNS midline intermediate target as well as in final targets such as muscles, it may function as an en passant neurotrophic factor.…”

Molecular Control of the Neural Crest and Peripheral Nervous System Development

“…Peripheral innervation targets, central neurons, and associated glia produce neurotrophic cues that direct the development of receptive neuronal subtypes at distinct stages (Davies, Thoenen, & Barde, 1986; Kawaja et al, 2011; Lumsden & Davies, 1983; Patapoutian, Backus, Kispert, & Reichardt, 1999; Usui et al, 2012). Neurotrophic factor responsiveness is highly dynamic during development.…”