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XB-ART-50197
J Neurosci March 11, 2015; 35 (10): 4366-85.

Endogenous gradients of resting potential instructively pattern embryonic neural tissue via Notch signaling and regulation of proliferation.

Pai VP , Lemire JM , Paré JF , Lin G , Chen Y , Levin M .


Abstract
Biophysical forces play important roles throughout embryogenesis, but the roles of spatial differences in cellular resting potentials during large-scale brain morphogenesis remain unknown. Here, we implicate endogenous bioelectricity as an instructive factor during brain patterning in Xenopus laevis. Early frog embryos exhibit a characteristic hyperpolarization of cells lining the neural tube; disruption of this spatial gradient of the transmembrane potential (Vmem) diminishes or eliminates the expression of early brain markers, and causes anatomical mispatterning of the brain, including absent or malformed regions. This effect is mediated by voltage-gated calcium signaling and gap-junctional communication. In addition to cell-autonomous effects, we show that hyperpolarization of transmembrane potential (Vmem) in ventral cells outside the brain induces upregulation of neural cell proliferation at long range. Misexpression of the constitutively active form of Notch, a suppressor of neural induction, impairs the normal hyperpolarization pattern and neural patterning; forced hyperpolarization by misexpression of specific ion channels rescues brain defects induced by activated Notch signaling. Strikingly, hyperpolarizing posterior or ventral cells induces the production of ectopic neural tissue considerably outside the neural field. The hyperpolarization signal also synergizes with canonical reprogramming factors (POU and HB4), directing undifferentiated cells toward neural fate in vivo. These data identify a new functional role for bioelectric signaling in brain patterning, reveal interactions between Vmem and key biochemical pathways (Notch and Ca(2+) signaling) as the molecular mechanism by which spatial differences of Vmem regulate organogenesis of the vertebrate brain, and suggest voltage modulation as a tractable strategy for intervention in certain classes of birth defects.

PubMed ID: 25762681
PMC ID: PMC4355204
Article link: J Neurosci
Grant support: [+]
Genes referenced: cacna1b ctrl emx1l foxg1 itih3 kcna5 notch1 otx2 slc6a4l tbx2


Article Images: [+] show captions
References [+] :
Abad, Reprogramming in vivo produces teratomas and iPS cells with totipotency features. 2013, Pubmed


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