Molecular guidance cues necessary for axon pathfinding from the ventral cochlear nucleus

Abstract

During development, multiple guidance cues direct the formation of appropriate synaptic connections. Factors that guide developing axons are known for various pathways throughout the mammalian brain; however, signals necessary to establish auditory connections are largely unknown. In the auditory brainstem the neurons whose axons traverse the midline in the ventral acoustic stria (VAS) are primarily located in the ventral cochlear nucleus (VCN) and project bilaterally to the superior olivary complex (SOC). The circumferential trajectory taken by developing VCN axons is similar to that of growing axons of spinal commissural neurons. Therefore, we reasoned that netrin-DCC and slit-robo signaling systems function in the guidance of VCN axons. VCN neurons express the transcription factor, mafB, as early as embryonic day (E) 13.5, thereby identifying the embryonic VCN for these studies. VCN axons extend toward the midline as early as E13, with many axons crossing by E14.5. During this time, netrin-1 and slit-1 RNAs are expressed at the brainstem midline. Additionally, neurons within the VCN express RNA for DCC, robo-1, and robo-2, and axons in the VAS are immunoreactive for DCC. VCN axons do not reach the midline of the brainstem in mice mutant for either the netrin-1 or DCC gene. VCN axons extend in pups lacking netrin-1, but most DCC-mutant samples lack VCN axonal outgrowth. Stereological cell estimates indicate only a modest reduction of VCN neurons in DCC-mutant mice. Taken together, these data show that a functional netrin-DCC signaling system is required for establishing proper VCN axonal projections in the auditory brainstem.

The emerging framework of mammalian auditory hindbrain development

“…A similar overlap of Wnt1-, Atoh1-and MafB-expressing cells is observed for the VCN, which provides the excitatory input to the MSO and LSO (Fujiyama et al 2009;Maricich et al 2009;Farago et al 2006;Landsberg et al 2005;Howell et al 2007). It will be interesting to study the implications of this shared genetic program for the evolution of sound localization circuits (Christensen-Dalsgaard and Carr 2008; Grothe and Pecka 2014).…”

Time-dependent Gene Expression Analysis of the Developing Superior Olivary Complex

“…They are essential for proper development of the inner ear, and Gata3 is additionally required for correct olivocochlear projections (57). Expression of Gata3 has also been reported in cochlear ganglion neurons (57), the lateral lemniscus, and the inferior colliculus (81), whereas Mafb/Kreisler is present in neurons of the ventral cochlear nucleus (82). Given these data, these TFs might provide a molecular mechanism for coordinated development of the auditory system.…”

Preferential localization of neural cell recognition molecule NB‐2 in developing glutamatergic neurons in the rat auditory brainstem

“…Netrin-DCC signaling is required to establish proper axonal projections from the VCN in mouse embryos (Howell et al, 2007). Eph/Ephrin signaling is also known to play an important role in establishing auditory brainstem circuits in chick embryos (Cramer et al, 2002(Cramer et al, , 2006.…”