Abstract
Axons are directed to their correct targets by guidance cues during neurodevelopment. Many axon guidance cues have been discovered; however, much less known is about how the growth cones transduce the extracellular guidance cues to intracellular responses. Collapsin response mediator proteins (CRMPs) are a family of intracellular proteins that have been found to mediate growth cone behavior in vitro; however, their roles in vivo in axon development are much less explored. In zebrafish embryos, we find that CRMP2 and CRMP4 are expressed in the retinal ganglion cell layer when retinal axons are crossing the midline. Knocking down CRMP2 causes reduced elongation and premature termination of the retinal axons, while knocking down CRMP4 results in ipsilateral misprojections of retinal axons that would normally project to the contralateral brain. Furthermore, CRMP4 synchronizes with neuropilin 1 in retinal axon guidance, suggesting that CRMP4 might mediate the semaphorin/neuropilin signaling pathway. These results demonstrate that CRMP2 and CRMP4 function differentially in axon development in vivo.
Highlights
The correct formation of neural circuits is critical for establishing a functional nervous system
We found that combining half doses of CRMP2 and CRMP4 MOs resulted in more axon growth defects than the sum of the defects caused by the two single half doses of morpholinos (Figure 5)
The study has revealed the intracellular mechanisms of how the Collapsin response mediator proteins (CRMPs) transduce the extracellular guidance cues into behavioral responses of the growth cone in vivo
Summary
The correct formation of neural circuits is critical for establishing a functional nervous system. The intracellular molecular response mechanisms underlying how the growth cone of axons interpret environmental guidance cues are relatively less understood. The collapsin response mediator protein (CRMP) is an intracellular protein discovered in a screen for components of the semaphorin 3A (originally named collapsin [3]) signaling pathway that mediates the collapse response of the growth cone [4]. Many studies have demonstrated that CRMPs are involved in growth cone collapse and axon growth in vitro [8, 10, 13, 16]. Their roles in axon development in vivo, in the Neural Plasticity central nervous system, still remain unclear. No anatomical or macroscopic changes in gross brain anatomy is observed in CMRP4 knockout mice [17, 18] a selective decrease of axon extension and reduced growth cone area are observed in the cultured hippocampus neurons of CMRP4 knockout mice [18]
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