BMP signaling specifies the development of a large and fast CNS synapse

Abstract

Large excitatory synapses with multiple active zones ensure reliable and fast information transfer at specific points in neuronal circuits. However, the mechanisms that determine synapse size in CNS circuits are largely unknown. Here we use the calyx of Held synapse, a major relay in the auditory system, to identify and study signaling pathways that specify large nerve terminal size and fast synaptic transmission. Using genome-wide screening, we identified bone morphogenetic proteins (BMPs) as candidate signaling molecules in the area of calyx synapses. Conditional deletion of BMP receptors in the auditory system of mice led to aberrations of synapse morphology and function specifically at the calyx of Held, with impaired nerve terminal growth, loss of monoinnervation and less mature transmitter release properties. Thus, BMP signaling specifies large and fast-transmitting synapses in the auditory system in a process that shares homologies with, but also extends beyond, retrograde BMP signaling at Drosophila neuromuscular synapses.

Comparative Analysis of Gene Regulatory Network Components in the Auditory Hindbrain of Mice and Chicken

“…Even Neat1 , a mammalian-specific gene with no ortholog in the chicken genome, showed no specific link to evolutionary novelties such as the DCN [Nieuwenhuys et al, 1998;Nothwang, 2016]. The absence of nucleus-specific expression is in line with previous RNA in situ hybridization-based expression analysis in the rodent auditory hindbrain, which showed rather widespread expression patterns for bone morphogenetic protein signaling molecules [Xiao et al, 2013] and >20 genes encoding different functional protein classes [Ehmann et al, 2013]. This similarity in gene expression might be unexpected in view of the different rhombomeric origins of the auditory nuclei.…”

“…Future studies should therefore either address TFs with low expression in the SOC or candidate genes from cell-typespecific transcriptome analysis. Such studies have already been pioneered for the bushy cells of the VCN [Körber et al, 2014], and the LSO and MNTB of the SOC [Xiao et al, 2013]. The possibility of labeling specific cell types using select reporter mouse lines [Fujiyama et al, 2009;Maricich et al, 2009] and the advent of techniques for transcriptome analysis of a few cells will promote this type of analysis [Tang et al, 2009;Hashimshony et al, 2016].…”

“…Furthermore, several reported functions render them attractive candidates for evolutionary and developmental processes in the auditory system. The TF Hoxd1 has been shown to confer mammal-specific features to neuronal circuits [Guo et al, 2011] and Mab21l2 modulates bone morphogenetic protein signaling [Baldessari et al, 2004] which is important for the development of large synapses in the auditory hindbrain [Xiao et al, 2013]. Mitf is associated with congenital sensorineural hearing loss [Tassabehji et al, 1994], raising the question of whether this TF belongs to the increasing number of proteins with a retrocochlear function as well, as recently proposed [Willaredt et al, 2014].…”

Recent advances in nanorobotic manipulation inside scanning electron microscopes

“…Some notable achievements are mechanical and electrical characterization of graphene membranes 28,45 , electrical measurement of single transistors 27 , 3D transfer of graphene 28,45 , assembly of photonic crystal devices 1,187 , identification of the size effect on the mechanical properties of nanowires and the strain effect on the piezoresistive properties of nanowires 51,162 , discovery of new gene loci associated with promyelocytic nuclear bodies 37 , and tracing of neuronal networks and synaptic connections 182,183 . The formation of hybrid systems by integrating other instruments into an SEM has also produced unique capabilities.…”

“…Using SBFSEM, the postsynaptic membrane of an axon that carries the 'winning' signal was reinforced. SBFSEM was also employed to investigate the role of bone morphogenetic proteins (BMPs) in synapse generation and development 183 . In the absence of BMPs, synapse elimination at the calyx of Held in a mouse brain did not occur normally, whereas control mouse neurons undergo normal synapse elimination in the presence of BMPs.…”