Cadherins regulate nuclear topography and function of developing ocular motor circuitry

Athene Knüfer,Jonathan Dw Clarke,Sarah Guthrie,Gregory S Walsh,Giovanni Diana

doi:10.7554/elife.56725

Athene Knüfer, Jonathan Dw Clarke + Show 3 more

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https://doi.org/10.7554/elife.56725

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Abstract

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

Highlights

During vertebrate embryonic development, neurons within the central nervous system (CNS) assemble into stereotyped anatomical structures, such as clusters or layers.Neurons which share common inputs and axonal outputs, including motor neurons of the brainstem and spinal cord, are often organised as coherent clusters of cells, termed nuclei.Despite their prevalence, little is known about the mechanisms regulating their development
We find that neurons belonging to the adjacent inferior oblique (IO) subnucleus, in which cadherin function is unperturbed, are mispositioned, suggesting that cadherin-mediated interactions between subnuclei contribute to their normal positioning
Developing ocular motor neurons differentially express cadherin combinations. In addition to their established roles in controlling motor neuron topography (Price et al, 2002; Astick et al, 2014), recent work indicates that type II cadherins act synergistically with the type I cadherin cdh2 (N-Cadherin) to control their precise positioning, the exact mechanism remains unclear (Dewitz et al, 2019)

Summary

Introduction

Neurons within the central nervous system (CNS) assemble into stereotyped anatomical structures, such as clusters or layers (laminae).Neurons which share common inputs and axonal outputs, including motor neurons of the brainstem and spinal cord, are often organised as coherent clusters of cells, termed nuclei.Despite their prevalence, little is known about the mechanisms regulating their development (nucleogenesis). Cadherin transcript detection was performed in transgenic Isl1:GFP zebrafish embryos, in which the majority of ocular motor neurons, including trochlear (nIV) and most oculomotor (nIII) neurons are known to express GFP

Results

Conclusion