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

AR055993-01 NIAMS NIH HHS , R01 AR055993 NIAMS NIH HHS

	Figure 1. A distinct and intense hyperpolarization of cells lining the neural tube exists before neural tube closure. A, Representative CC2-DMPE:DiBAC staining (Aiii, Aiv) of indicated regions (Ai, Aii) of Xenopus embryos at stages 16 and 18. Blue arrows mark the cluster of intensely hyperpolarized cells in the anterior neural field. (Figure legend continues.)(Figure legend continued.) The hyperpolarization begins well before the neural tube closure (N 23 embryos). Illustrationsreproducedwith permissionfromNieuwkoop and Faber, 1967). B, Fluorescence intensity measurements of CC2-DMPE:DiBAC-stained embryo along the indicated axis (white line in inset) at multiple time points (t1–t7) during development from stage 14 –20. Representative set of measurements from among 10 different embryos analyzed (C) showed the transformation of broad low-intensity hyperpolarization becoming focused highintensity hyperpolarization before diminishing to background levels during neurulation. C, Quantification of CC2-DMPE:DiBAC peak fluorescence intensities at each of the time points (stages 14 –20) in developing embryos (n 10). A one-way ANOVA analysis showed that at time point t4 the peak fluorescence intensity is significantly different than t1 and t7. Data are presented as mean SEM, ***p 0.001. D, Electrophysiological Vmem measurements of cells stainedwith CC2-DMPE:DiBAC in areas as indicated. Readingswererecordedfromfive embryos. Values are plotted as mean SEM. Data were analyzed by pairedt test andp 0.0001.
	Figure 2. Local perturbation of Vmem disrupts endogenous brain development. A, CC2-DMPE:DiBAC staining of stage 16 Xenopus control (uninjected) and Kv1.5, GlyR(IVM), or only GlyR microinjected (two dorsal cells at four-cell stage) embryos. Control embryos (n 28; Ai) and only GlyR(n 34; Aiv)-injected embryos showed characteristic hyperpolarization within the forming neural tube (blue arrow) but theKv1.5-injected embryo (Aii) shows widespread hyperpolarization [n 24, 21 embryos (87.5%) show changed Vmem] and the GlyR(IVM, in standard saline) embryo (Aiii) shows widespread depolarization [n 27, 18 embryos (66.7%) show changed Vmem]. Av, Fluorescence intensity measurements of CC2-DMPE:DiBAC-stained embryos. One-way ANOVA analysis pixel distance 100, 250, and 400,shows significant difference of CC2-DMPE:DiBAC signal in the Kv1.5 and GlyRIVM embryos compared with control embryos. Data are represented as mean SEM; ***p 0.001 and **p 0.01.B,Quantification of tadpoleswith brain phenotypes upon microinjections of Kv1.5 or GlyR(IVM 70mMCl ) ion channel mRNA in the two dorsal cells (red arrows) of the four-cell Xenopus embryo. A high incidence of malformed brain is observed in dorsal injections compared with uninjected controls. A 2 analysis showed that the too-hyperpolarized and the too-depolarized embryos were significantly different from the rightly polarized controls. ***p 0.001.C, Four-cell Xenopus embryos were injected (red arrow indicates injected cell).Ci, Stage 45 uninjected control tadpoles show well formed anterior neural tissue with red arrowheads indicating nostrils, orange arrowheads indicating forebrain/olfactory bulbs, yellow arrowheads indicating mid brain, and green arrowheads indicating hindbrain.Cii, Stage 45 tadpole injected with hyperpolarizing channel Kv1.5in both the dorsal cells at the four-cell stage. The green arrowheads indicate the hindbrain, which remains largely unaffected. Blue arrowheads indicate severely malformed midbrain and forebrain. Eyes were also (Figure legend continues.)(Figure legend continued.) found to be malformed or absent. Ciii, Stage 45 tadpole that had been injected with hyperpolarizing Kv1.5 in only one dorsal cell of four-cell embryo with the otherside as contralateral control. The uninjected side of the embryo shows unaffected nostrils, forebrain, midbrain, and hindbrain (arrowhead colors as in Ci). The injected side of the embryo shows misformed nostrils and forebrain/olfactory bulb (blue arrowheads) but unaffected midbrain and hindbrain. D, Stage 45 PNTub::GFP transgenic tadpole shows GFP fluorescence in neural tissue (arrowhead colors as in Ci). Gut autofluorescence is also seen as indicated. Di, The uninjected control tadpole shows intact nostrils, forebrain/olfactory bulbs, midbrain, and hindbrain. Dii, Stage 45 tadpoles injected with Kv1.5 ion channel mRNA in one dorsal cell at the four-cell stage, with the contralateral side of the brain as control (as in Ciii). Blue arrowheads indicate the malformed nostrils and forebrain/olfactory bulbs regions in the injected tadpole (n 100). Black spots are melanocytes.
	Figure 3. Local perturbation of Vmem signal disrupts endogenous forebrain marker expression during neural development. A, Control (Ctrl; uninjected) embryos at the indicated stage (Ai, Aiii, Av, Avii, Aix) and embryosmicroinjected(Inj)with Kv1.5mRNA(Aii, Aiv, Avi, Aviii, Ax) intheright dorsal cell atthefour-cellstage. Insitu hybridizationforemx(Ai, Aii[n 7 of 10], Avii, Aviii[n 10 of 14]),bf1(Aiii, Aiv[n 6 of 9], Aix, Ax[n 6 of 9]), andotx2(Av, Avi [n 9 of 13])show asignificantly decreased or missing expression (red arrowheads) ofemx,bf1, andotx2only on the injectedside of the embryos, while expression on the uninjected (Uninj)side is intact (green arrowheads). Quantification of thein situsignal (Axi–xiii) as ratio of thesignal intensity for uninjected verses its contralateral injectedside for emx (Axi), bf1 (Axii), and otx2 (Axiii)show asignificant change in theinsitusignal for these probes upon Kv1.5mRNA injection. The data are represented as mean SEM(n 8 for each). The data are analyzed viattest. ***p 0.001. B, Control(untreated) embryos(Bi, Bv, Bix), embryostreated with LiCl(0.2 M for 10min at 32-cellstage; Bii, Bvi, Bx), UV light (75 s; Biii, Bvii, Bxi) and microinjected with Kv1.5 mRNA in the two dorsal cells at four-cell stage (Biv, Bviii, Bxii). Phase contrast images (Bi–iv) of embryos at stage 30 show that LiCl treatment (Bii) dorsalizes the embryos with a majority of dorsal tissue and lack of ventral tissue development, while UV treatment (Biii) ventralizes the embryos with increased ventral tissue specification and lack of dorsal tissue development as compared with control embryos (Bi), whichshow correctly balanced development of dorsal and ventral tissues.Kv1.5-injected embryos (Biv) appear normal similar to control embryos with balanced development of dorsal and ventral tissues. In situ hybridization for dorsalization markers chordin(Bv–viii) andcerberus (Bix–xii) show normal expression (green arrows) in control embryos (Bv, Bix), a significantly increased expression (yellow arrows) in LiCl-treated embryos (Bvi [n 9 of 10], Bx [n 9 of 9]), a significantly decreased expression (red arrow) in UV-treated embryos (Bvii [n 14 of 15], Bxi [n 11 of 11]), and relatively unchanged expression (green arrows) in Kv1.5-injected embryos (Bviii [n 20 of 20], Bxii [n 18 of 18]) compared with control embryos.
	Figure 4. The Vmemsignal istransduced via Ca2 and GJ. A, Schematic ofthe logic behindthesuppressionscreentotest known candidate mechanisms for transduction of Vmem change to malformed brain tissue phenotype in tadpoles: GJ,serotoninsignaling, and calcium influx. B, Quantification of tadpoles with malformed brain phenotype in control (GFP-injected) and Kv1.5- microinjected (dorsal two blastomeres at four-cell stage) embryos with or without the indicated inhibitors. A high incidence of malformed brain phenotype isseen in Kv1.5-microinjected embryos andthis effect ofKv1.5is prevented by verapamil(a blocker of voltage-gated calcium channels, stages 10 –30), Lindane (a blocker of GJC among cells, stages 10 –30), and H7 (a chimeric dominant-negative connexin that blocks GJ) but not by fluoxetine (Flx) or sertraline (chemical blockers of the serotonin transporter, stages 10 –30) or dominant-negative SERT (DN-SERT) mutant (molecular blocker of serotonin transport). A one-way ANOVA (n  3 experiments) analysis with post hoc test showed significant variance among the groups, with Kv1.5significantly different from control,Kv1.5 verapamil,Kv1.5 Lindane, andKv1.5 H7. ***p 0.001, **p 0.01.
	Figure 6. Vmemmodulationpotentiates abilityofreprogrammingfactorsto induce ectopicneuraltissues.A,Quantificationoftadpoles with ectopic neural tissue in control embryos (uninjected; Uninj) and embryos microinjected with POUHB4mRNA in both cells at the two-cellstage. Coinjection with the hyperpolarizingKv1.5channels caused asignificant increase in the number of tadpoles with ectopic neuraltissue comparedwithPOUHB4-only controls.A2 analysisshowedthatthePOUHB4-only controls aresignificantlydifferent fromPOUHB4Kv1.5.**p 0.01.B,Stage45PNTub::GFPtransgenictadpoles(Bi–viii).Bi,Biv,andBviarebright-fieldimages.Bii, Biii,Bv,Bvii,andBviiiareGFPfluorescence.Control(uninjected)embryos(Bi–iii)showwellpatternednostrils,forebrain/olfactorybulbs, midbrain, hindbrain(arrowhead colorssame asFig. 2Ci), andspinal cord(Biii; white arrowheads). Tadpoles injected with POUHB4 hyperpolarizingKv1.5(Biv–viii) showed brain tissue that was highly expanded anteriorly (Biv; yellow arrows), noticeable amounts of ectopic neural tissue in the head unattached to the brain (Bv; yellow arrows), and noticeable ectopic neural tissue in the tail (Bvi—viii; yellow arrows) away fromthespinal cord(white arrowhead).
	Figure 7. Identity of ectopic neural tissue induced by Vmem modulation was confirmed by in situ hybridization for developing brain-tissue markers. In situ hybridization for forebrain markers emx (ii–viii) andbf1(ix–xv) of stage 30 control embryos (i–iv [n 7], ix–xi [n 11]) and embryos microinjected (both cells at two-cell stage) with POU HB4 Kv1.5ion channel mRNA (v–xv) [emx:n 8 of 15; bf1:n 6 of 12]. The areas marked by white squares in ii,v,vii, ix,xii, andxivare expanded in iii, iv, vi,viii,x,xi,xiii, andxv, respectively. Red arrows mark ectopic expression and green arrowheads mark the endogenous normal signal; especially striking was the appearance of brainmarker-positive tissues intheflank and mid-body dorsal fin(xv;red arrows).
	Figure 8. Ectopic neuraltissue induction by Vmem is local but initially not cell autonomous. A, Insitu hybridization for forebrain markersemx(Ai) andbf1(Aii; blue) ofstage 30 embryosthat were microinjected(both cells attwo-cellstage) with POUHB4Kv1.5--galactosidasemRNA(red).-Galactosidasestain was developed usingMagenta-Gal(red/magenta)substrate. Atthisstage Magenta-Galsignal andemx/bf1 insitusignal overlapwith each other, although not perfectly; especially notable areregionswhere ectopic bluesignal(yellow arrowheads; neuralmarkerexpression) is next to, but not overlapping with, the misexpressed ion channel (black arrowheads; Magenta-Gal), indicating that not only hyperpolarized cells but also their neighbors are initially driven to turn on neuralmarkers.B,Atypicalstage 45tadpolethat had beenmicroinjectedwith POUHB4Kv1.5-EGFPshowsthat bythisstage, ectopic neuraltissues induced inthe head(Bi,Bii) andtail(Biii, Biv; yellow arrows) are always positive for the EGFP signal indicating hyperpolarizing ion channel expression (this was true in 100% of embryos examined [n  20]). Thus, (Figure legend continues.)(Figure legend continued.) by stage 45, any neighboring cells that were not hyperpolarized have turned off the aberrant neural markers, and only cells that were expressing the channel remain and form ectopic brain. Conversely, at both stages, we observed expression of the hyperpolarizing channel insome regions in which it was notsufficientto induce neural markers or ectopic brain.C, A model forde novo neural tissue induction by Vmem change was formulated to explain the local but initially not cell-autonomous misexpression of neural fate induced by hyperpolarization. This model is based on cellssharingtheir resting potentialthrough GJs. Such electrical coupling of cells has been documented during neural induction and within the developing neural plate cells (Properzi et al., 2013) with the transfer of Vmem signals occurring to the surrounding cells through these GJ couplings (Blackshaw and Warner, 1976;Shi and Borgens, 1995). As cell fields become partitioned into more finely defined regions with developmental age, large areas of GJ connections are progressivelyshut down to isolatespecific groups of cells with different fates and to insulatesuch isopotential groups from the long-rangesignals (Warner, 1985, Fig. 8C). Early pluripotent embryonic cells are connected by GJ to form isopotential cell clusters with respect to Vmem (Ci). Introduction of an ion channel in one cell results in the hyperpolarization of the Vmem of that cell (Cii). As the cell adopts a neural fate and turns on expression of neural markers (Ciii), GJs spread this hyperpolarization to coupled neighbors, causing them also to express the observed ectopic neural markers even though they were not injected with the channel (Civ). As embryonic development proceeds, the tissues become progressively more subdivided with respect to gap junctional connections (Cv). As coupling is reduced, the uninjected cells lose the temporarily hyperpolarized Vmem and then revert back to their original non-neural fate, whereasthe injected cells retaintheir new/changed Vmem giving rise tode novo neural tissues detected at much later stages (Cvi).
	Figure9. LocalanddistantVmemsignalsregulatetheproliferationinthedevelopingbrain.A,Agarosesectionsofstage30 control(uninjected)embryos(Ai)andembryosmicroinjectedwithhyperpolarizing Kv1.5mRNA(Aii,Aiii) inthe indicated blastomeres(red arrows) atfour-cellstage[n 11for each group including controls]. Immunostaining ofsectionsthroughthe developing brainwithH3P(Ai–iii)shows a distinct change in the H3P (orange arrowheads) staining in the developing brains of microinjected embryos with highly increased H3P staining in theventral-injected embryos compared with uninjected controls.B,QuantificationofH3Pimmunostainingintheagarosesectionsthroughdevelopingbrainsofstage30control(uninjected)andKv1.5microinjected(redarrowsindicateinjectedblastomeresatfour-cell stage)embryos.DorsalblastomereinjectionssignificantlydecreasetheH3PsignalwhereasventralinjectionssignificantlyincreasetheH3Psignal.ValuesaremeanSEM(n10);*p 0.05,**p 0.01,and ***p 0.001 one-wayANOVAwith post-test.C,Agarosesections of Fucci-microinjected(both cells attwo-cellstage)stage 30 control embryos(Ci) and embryos alsomicroinjectedwith hyperpolarizingKv1.5 mRNA(Cii,Ciii)intheindicatedblastomeres(redarrows)atfour-cellstage[n12foreachexperimentalgroup].Fluorescencedetectioninsectionsthroughthedevelopingbrain(Ci–iii)showsadistinct change in the cells’ fluorescence pattern (indicator of their placement in differentstages of cell cycle; green, S/G2/M; red, G1; yellow, S) in the developing brains of microinjected embryos, with decreased numbers of green and yellow fluorescent cells (S/G2/M phase-dividing cells) and increased red fluorescent cells (G1 nondividing cells) in the dorsal-injected embryos (Figure legend continues.)(Figure legend continued.) (Cii), and increased numbers of yellow fluorescent cells (G1 to S phase– cells entering division) in ventrally injected embryos(Ciii), compared with controls(Ci). D, Quantification of Fucci fluorescence (green, red, and yellow) in the agarosesections through developing brains of stage 30 controls (only Fucci-injected) and Kv1.5 (in addition to Fucci)- microinjected (red arrows indicate injected blastomeres at four-cell stage) embryos.Kv1.5microinjectionsignificantly changes the fluorescence pattern of cells compared with the controls. Dorsal blastomere injections significantly decrease green fluorescence and significantly increased red fluorescence whereas ventral blastomere injections significantly increase yellow fluorescence. Values are mean  SEM (n  12); *p 0.05, **p 0.01, and ***p 0.001; two-way ANOVA with post-tests.E, Quantification of H3P immunostaining in the agarose sectionsthrough developing brains ofstage 30 control(uninjected) andKv1.5mRNAmicroinjected into two ventral blastomeres at four-cell stage embryos. Injected embryos were kept with or without the indicated inhibitors. A high incidence of H3P signal is seen in the brain tissue in Kv1.5 microinjected embryos and this effect ofKv1.5is prevented by Lindane (stages 10 –30) and H7 (respective pharmacological and chimeric dominant-negative blockers of GJC among cells) but not by fluoxetine (Flx; stages 10 –30) or dominant-negative SERT (DN-SERT; a chemical blocker and molecular blocker of the serotonin transporter, respectively) or verapamil (stages 10—30; a blocker of voltage-gated calcium channels). A one-way ANOVA (values are mean  SEM; n  10) analysis with post hoc test showed significant variance among the groups, with Kv1.5significantly different from control andKv1.5 Lindane andKv1.5 H7 (***p 0.001).F, Model for Vmem control of neural tissuesize by regulating proliferation over long range. The set of studies reported here show that there is a specific degree of hyperpolarized resting membrane potential within the developing neural tissue, with the surrounding tissue depolarized (Fi). Thisspecific degree of hyperpolarized potential regulates the proliferation within that tissue as disrupting this specific hyperpolarization signal decreases the proliferation in the brain. Concurrently, the surrounding depolarized tissues restrict proliferation in the brain tissue over long distance thus governing the tissue size and sculpting the brain tissue (Fii). Hence, when the surrounding tissue is hyperpolarized this restriction is lost and there is increased proliferation in the brain tissue observed (Fiii). These ectopic hyperpolarized tissues not only induce ectopic brain tissues but also might regulate the proliferation within these ectopic brain tissues in conjugation with the surrounding depolarized tissue to bring about sculpting these ectopically induced brain tissues. These results suggest an important role of resting potential distribution in regulating brain tissue size and sculpting.
	Figure 10. Synthesizing model for Vmem regulation of brain morphology. Model for VmemNotch integration in directing brain morphology. The set of studies reported here show that specific resting potential change is important for induction of neural tissue. Such a Vmemmediated signal is strong enough to rescue inhibition of neural tissue induction by the constitutively active notch on brain morphology, suggesting cross talk with notch pathway. Notch, however, isshownto depolarize Vmem,resulting in a feedback loop. Our data alsoshowthatthe Vmem signal is transduced via calcium and GJs, and also regulates the brain development transcription factors. Together, previous data and our new observations suggest the model schematized here for the interaction of two key factors— biochemical signaling via Notch and bioelectrical signaling via resting potential—in regulating the events that pattern the vertebrate brain.

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