Research Activities

Coordinated regulation of neural development by the neuroepithelial polarity factors

The development of the nervous system needs to be stringently orchestrated, since neural function relies on precise connections being made between neurons and their targets. Defects in neural development result in neurologic diseases. For example, lissencephaly with cerebellar hypoplasia is caused by disruption of the glycoprotein Reelin. Neuroepithelial cells are highly polarized neural stem cells that control various aspects of neural development, such as neurogenesis and the guidance of neural migration and axons. For the establishment of a functional nervous system, the coordinated control of neuroepithelial functions and morphology are crucially important (Wada et al. 2006, Development, Figure 6). However, the molecular mechanism underlying this coordination program remains unclear.

  The vagus nerve controls various body functions, including heart beat and gastrointestinal movement. We have studied the formation of vagus motor nuclei as a novel model system to study the molecular mechanisms underlying neural development. Using the transgenic zebrafish line Tg(CM-isl1:GFP)rw0, hereafter referred to as isl1:GFP, which expresses green fluorescent protein (GFP) in the motor neurons, including the vagus motor neurons, we identified several mutant lines in which the formation of vagus motor nuclei was affected (Ohata et al., 2009, Development, Figure 7). One of these variants has a mutation in the neuroepithelial polarity gene, with the result that the directionality of migration of vagus motor neuron precursors is random in this mutant. Analysis of the molecules acting downstream of this factor revealed that a neuroepithelial polarity complex coordinately regulates neuroepithelial polarity and neurogenesis (Ohata et al., 2011, Neuron). These results showing that mutation of a component of the neuroepithelial polarity complex results in a neural development disease increase our understanding of neuropathology.

Figure 7 Time-lapse imaging of the vagus motor nuclei formation
(A) isl1:GFP transgenic zebrafish that express GFP in motor neurons. (a) dorsal view (b) cross section at the broken line shown in (a)
(B) Method for time-lapse imaging of the vagus motor nuclei formation
(C) Time-lapse imaging of the development of the vagus motor nuclei

a. WT
b. towhead
c. towhead + mRNA

(D) Movies of Time-lapse imaging (a) wild-type (b) towhead mutant that affect a sugar modification pathway (c) towhead mutant injected with mRNA of the responsible gene