Adams DS , Uzel SG , Akagi J , Wlodkowic D , Andreeva V , Yelick PC , Devitt-Lee A , Pare JF , Levin M .

R01 AR061988 NIAMS NIH HHS , R01 HD081326 NICHD NIH HHS

             ATP-sensitive potassium channel complex

	Figure 1. External craniofacial anomalies characteristic of Andersen-Tawil Syndrome. One of the three features used for diagnosis of ATS, craniofacial anomalies are seen in a majority of patients. These features are variably penetrant, however, with different patients showing different degrees of severity and different subsets of those shown. The characteristics shown here are frequently mentioned; a more inclusive list can be found in Yoon et al. (2006).
	Figure 2. WISH for KCNJ2 in Xenopus and mouse embryos Species are indicated on the left. A, a dorsal-anterior view of a stage 14 Xenopus embryo dehydrated in methanol following fixation. The KNCJ2 signal is much lighter in the midline and two oval areas on either side at the anterior end, the area outlined by white dots. B, a neurulating Xenopus embryo showing KCNJ2 signal on the anterior neural folds (lower green arrows). Upper green arrow points to expression at the approximate position of the second pharyngeal cleft. Inset is sense strand control. C, stage 27 Xenopus embryo showing strong KCNJ2 staining in the somites (green arrows). Inset is sense strand control. D, in situ hybridization of KCNJ2 mRNA expression in an E8.5 mouse embryo (dorsal view of whole-mount embryo). KCNJ2 mRNA is detected in the midline of the fusing neural tube, and in a punctate bilateral expression pattern lateral to the midline and in anterior neural tissues (green arrows). E, lateral view of whole-mount embryo at E9.5 showing KCNJ2 mRNA expression in the craniofacial region including the frontonasal prominence (fnp) and branchial arches 1 and 2, and in the forming somites (green arrows). F, sectioned ISH of E9.5 mouse embryo revealed KCNJ2 expression in the epithelium of the frontonasal prominence (fnp) (green arrows). A schematic in the right top corner indicates the approximate plane of section. G, lateral view of whole-mount embryo craniofacial region at E10.5 revealed KCNJ2 expression in the frontonasal prominence (fnp), in the mandibular process (ma) (green arrow) including along the border with the maxillary process (mx). H and I, sectioned ISH revealed KCNJ2 mRNA expression in neural crest-derived mesenchymal cells of the palatal shelves (ps), in mesenchymal cells surrounding the developing Meckel's cartilage (m) and in the olfactory epithelium of nasal cavity (nc) in E13.5 (H) and E15.5 (I) embryos (green arrows). Inserts adapted from d'Amaro et al. (2012). J, at E12.5 KCNJ2 mRNA was detected in condensations of the developing forelimb digits (green arrows). Abbreviations: ba1, branchial arch 1; ba2, branchial arch 2; fb, forebrain; fnp, frontonasal prominence; m, Meckel's cartilage; mb, midbrain; ma, mandibular process; mx, maxillary process; nc, nasal cavity; ns, nasal septum; ps, palatal shelf; t, tongue.
	Figure 3. Tadpole craniofacial anomalies caused by injection of mRNA for KCNJ2 variants. Anterior is up in all panels; view is dorsal except in D–F, J, M, Q and U. All scale bars = 0.5 mm. A-F, normal wildtype head of the stage 46 tadpole. A and D, darkfield; B and E, Alcian blue staining; C and F, after Reisoli et al. (2010). G–U, both the range of phenotypes seen and the commonality of the phenotypes resulting from all the variants tested. G–K, heads of tadpoles that were injected with the dominant negative Kcnj2 variant D71V. Illustrated are typical anomalies: G, small eye; H, fusion of the two olfactory bulbs; I, pigmented optic nerve and missing eye; J, anomalies restricted to one side include a small misshapen eye with misplaced lens, grossly undersized branchial arches and malformed Meckel's cartilage; K,fusion of the brain eye and olfactory bulb on the right side. L–P, heads of tadpoles injected with T192A. L, the leftmost arrow points to a malformed olfactory bulb, while the other two arrows point to the same anomalies seen in D71V-injected tadpoles J and K, namely malformed Meckel's cartilage and fusion of the brain with the eye. M, another commonly seen malformation is the narrowing of the anterior most end with malformed or absent infraostral [sic infrarostral] and Meckel's cartilages. N, an example of a more subtle phenotype of differences in size of Meckel's cartilages and the branchial arches. O, a commonly seen eye phenotype, shown in an tadpole with bilateral anomalies. In these tadpoles the optic nerve is both pigmented and thickened, looking like an extension of the eye. This embryo also has a malformed olfactory bud [sic bulb]. P, this embryo shows the same inequality of Meckel's cartilages seen in N, combined with gross malformations of both eyes. The otic capsule is also misshapen in this tadpole. Q and R, tadpoles expressing the Y242F variant. Q, the ceratohyals of this tadpole are badly distorted, while at least one of Meckel's cartilages is located in the wrong place. The right eye of this tadpole lacked a lens. R, a more subtle effect of Y242F showing distorted ethmoidal plate, a badly positioned eye, and, like the D71V tadpole in J, small branchial arches on one side. S, similar phenotypes are caused by injection of a different potassium channel, including abnormal narrowing anteriorly and concomitant loss of Meckel's cartilages and probably the infraostral cartilage [sic infrarostral), fusion of the olfactory bulb and eye, misshapen eye, and a misshapen otic capsule, like the T192A-injected tadpole in P, which lacks an otolith. T and U, tadpoles grown from R218W-injected embryos. T, this tadpole has distorted Meckel's cartilages and quadrate, malformed eyes, malformed ethmoidal plate, and small branchial arches on one side. U, deformed Meckel's and ceratohyal cartilages, one bad eye and small branchial arches, resulting from R218W injection as well as injection of the other variants.
	Figure 4. Box and whisker plots illustrating the differences in proportions of CFAs resulting from injections of different mRNAs. Box plots show median and 1st and 3rd quartiles; the whiskers extend to the 10th and 90th percentiles; the dot indicates the mean. Controls are shown in yellow, KCNJ2 variants in red and other translocators in orange. None of the control mRNAs (β-gal, GlyR, NHE3) caused a meaningful increase in the proportion of CFAs; the mean proportion of CFAs in negative controls was 14%. All the variants of KCNJ2 caused greater than 30% of tadpoles to develop CFAs, well above our threshold of 24% for biological significance; all of these differences were highly significant (Table 3). Two other potassium channels, Kir6.2 (KCNJ11) and KvLQT (KCNQ1), plus a light-activated cation channel (ChR2-D156A) and a light-activated hydrogen ion pump (Arch) likewise caused meaningful increases in the proportion of tadpoles developing CFAs.
	Figure 5. Skeletal muscle phenotype caused by injection of mRNA for variant KCNJ2. Images of the skeletal muscle phenotypes observed in injected tadpole tails; in A–C anterior is to the left and dorsal is up, in D–G anterior is to the right and dorsal is up and in H–L anterior is up. A, live tadpole tail imaged using polarized light. Normal muscles, indicated by the green arrows, yield clear, organized, light patterns. In contrast, abnormal muscles are obviously disordered. B, expression of D71V-tdTomato in the same tail. C, overlay of A and B shows the overlap of variant KCNJ2 expression with the position of abnormal muscle structure, and its absence from the normal muscle (now pseudocoloured green). D–G, a comparison of the organization of fibronectin in normal tails versus tails injected with variant KCNJ2 lacking a fluorescent protein. In the injected animal (F, G) the normal pattern of expression has been severely disrupted, although the muscles look normally organized in brightfield. H, polarized light image of an R218W-injected animal that nonetheless shows normal organization of the tail muscles. I and J, tails from R218W-expressing tadpoles show characteristic alterations to the normal chevron pattern of the muscle blocks. Red arrows indicate especially large deviations. K and L, tails from T192A-expressing tadpoles also display the same types of deviations from the normal morphology, illustrating a similarity of muscle phenotypes that parallels the similarity of CFAs induced by different variants.
	Figure 7. Whole-mount ISH for well-known markers of craniofacial development in embryos injected with mRNA encoding D71V. Shown is a subset of the WISHs performed (see also Supplementary Fig. S3). This set represents at least two markers each of the relevant tissues, i.e. neural crest and the three placodes studied. A, chart showing locations of marker expression. B, normal (1st column), over-expressed (2nd column) and under-expressed (3rd column) examples from each of five representative markers. Red arrows point to positions of abnormal signal patterns; the green arrow in v points to normal expression on the side opposite the disrupted pattern. The patterns we saw, even in injected embryos that did not have significantly more misexpression than background, are consistent with incorrect or incomplete differentiation (ii, iii, v, vi, viii, ix) and anomalies in neural crest migration (xi, xii, xiv, xv). To date, we have not detected any correlation between the types or magnitudes of disruptions caused and the identity of the ion flux-perturbing construct injected.
	Figure 8. CFA induction. A, diagram illustrating our hypothesis about how either depolarizing or hyperpolarizing a cell membrane away from the optimal Vmem for the downstream effectors can lead to the same effect on phenotype. In every cell membrane, flux through ion channels, such as Kir2.1, or pumps sets the resting potential of the membrane. Vmem influences downstream effectors by affecting activity levels, in much the same way that temperature influences protein activity, and deviation from the optimum lowers activity. The example in this graph shows an effector that works optimally at a Vmem we have assigned the colour yellow, and drops off rapidly either above or below that value. The embryo-wide distribution of all of the cells’ Vmem values (e.g. Fig. 6C) is the regionalization that we call the ‘electric face’. To illustrate how gain- and loss-of-function variants, acting in a subset of individual cells, might disrupt the wild-type pattern and lead to dysmorphia, we have schematically represented changes to ‘Vmem’ by using Photoshop to artificially change the colours that represent the different Vmem values. The three circular representations of embryos are pseudocoloured copies of the wild-type embryonic Vmem pattern shown in Fig. 6C. The first is the wild-type pattern. The upper illustration represents how inhibition of Kir2.1 on the right-hand side would result in depolarization of that side, as represented by orange, while the lower represents hyperpolarization (green) due to gain of Kir2.1 function. On each of the three schemes is a circle indicating the position of the cells that will form the area between the right eye and the brain. The lack of signalling by downstream effectors in these regions leads to abnormal morphology of the tadpole; the hyperpolarized and the depolarized conditions give rise to the same phenotype because both changes move the Vmem out of the range that permits protein activity. The micrographs at the far right side are photos of actual tadpoles that were treated as indicated: the top tadpole was injected with the loss-of-function variant D71V, the bottom with the gain-of-function variant Y242F. B, a comparison of the proportion of D71V and WT injected tadpoles with misexpressed patterning genes (blue bars), versus the proportion with CFAs (red bars). Data on abnormal WISH patterns were pooled, and thus blue bars represent totals (see Table 4 for statistics); CFAs were counted for each of the biological replicates separately, and therefore the red bars represent means. Only three expression patterns were found to be significantly affected by expression of a variant, Otx2, Six1 and FoxE4 (Table 4). The number of CFAs was found to exceed the number of cases of misexpression of any single patterning gene. C, optogenetics can be used to manipulate Vmem. Expression of the light-activated cation channel ChR2-D156A causes a higher number of CFAs when injected embryos are exposed to blue light. Because we found evidence that Arch depolarizes in the dark, we compared Arch in the light to the results of pairing Arch with the constitutively active H+ pump PMA1, a protocol that reduced the dark phenotype. Box plots as in Fig. 4. D, optogenetics can be used to explore the timing of important electrophysiological events. Exposure to light causes an increase in the number of CFAs in embryos expressing Arch only if exposure occurs during early neurulation. The same exposure at later stages has no effect on craniofacial morphology (Table 3).
	Figure 9. Schematic of hypothesis. Transcription of KCNJ2 in the embryonic face, together with other ion channels, establishes endogenous patterns of Vmem across the anterior ectoderm. This pattern can be disrupted by changes in KCNJ2 expression, intracellular localization or gating properties, all of which can be induced by KCNJ2 variants. Because these voltage patterns regulate transcription of downstream genetic targets known to be important for patterning the face, this model predicts how KCNJ2 channelopathies result in craniofacial dysmorphias. As Vmem can be altered by many distinct channels, these findings suggest a novel control point for therapeutic intervention, using optogenetics and/or ion channel drugs to manipulate non-neural bioelectric signalling during embryogenesis and perhaps restore normal patterning despite KCNJ2 variants or other channelopathies.
	Fig. S1. (A) Components of a system for using optogenetics in Xenopus (not to scale). This custom optogenetics station was built on an existing microscopy platform consisting of a Nikon AZ100 stereo microscope with an Intensilight mercury illumination source, a Volpi LED brightfield light source and a Ludl MAC5000 XYZ stage controller. The additional commercial component was a Lumencor Spectra4 LED light source with a fibreoptic light guide. This provides illumination at four wavelengths, shown as an inset above the machine. Custom equipment included an adaptor to feed the Spectra 4 fibreoptic cable into the microscope via the fluorescence input port on the top rear of the scope; the light path is represented here by a purple line. Included in the adaptor is an easily accessible slot for a changeable baffle with an aperture that can be made to any size, thus allowing fine control over the size of the spot of light reaching the specimen. After passing through the aperture, the light is reflected down through the 5× objective, further reducing its diameter (not shown), then onto the specimen. The second custom component is a bracket for holding a fluid-filled light guide coming from the Intensilight. The bracket feeds the white light past an interchangeable band pass filter (a filter that allows green light through is shown). The light from this source is not focused, but rather can be used to illuminate the entire embryo. This feature was added to allow simultaneous activation or deactivation of all the light-gated translocators that might be expressed, while the pinpoint of light coming through the objective allows precision and aiming of the spot towards a particular feature of interest without illuminating other channels. The final custom component is a DAQ board that allows the computer, running NIS Elements, to control all the components, allowing versatile and fine control over location and timing of illumination. (B) A red spot generated by the red Spectra 4 LED, shining on a standard business card, to show shape, and (C) as seen on the monitor to show size. The innermost ring indicates a 100 μm radius. (D) A Xenopus gastrula-stage embryo expressing EOS-FP, a fluorescent marker that undergoes a permanent change from green to red when exposed to UV light. We used this technique to illustrate how the LED light can illuminate a small area without affecting the rest of the embryo. Black and white: the embryo under bright-field illumination; the embryo is approximately 1.2 mm in diameter. Green: EOS-FP fluorescence everywhere except the spot in the middle that was illuminated with the UV Spectra4 LED for 6 s. Red: the EOS-FP that has been converted to red by UV illumination. The spot is 200 μm in diameter.
	Fig. S2. (A) Chip used to hold the embryos in place for time-lapse imaging and/or repeated exposure to light. The trap (Adams et al. 2014; Zhu et al. 2014) is made of PDMS and has been filled with blue dye to show the shape of the microfluidics chamber. White arrows indicate the direction of flow of medium circulated by a peristaltic pump (not shown) at 5–10 ml min−1. The channel is surrounded by a second channel (lighter blue ink) that is connected to a vacuum; this vacuum channel seals the chip to the plastic sheet and prevents leaks. (B) A close up showing an individual embryo slot. White lines indicate the widths of the openings facing the channel; the difference leads to the pressure gradient that holds the embryos in place (direction indicated by arrow). (C) Image of a chip with embryos in each slot. Also visible are the attached tubes bringing medium to the chip.
	Fig. S3. WISH for craniofacial patterning genes in embryos injected with the dominant negative (DN) D71V mRNA and with WT KCNJ2. Ten markers were used to characterize the effect of the DN and WT KCNJ2s on craniofacial patterning. The marker is indicated to the left of each row; two columns of images each are presented for untreated controls (No Treatment), embryos injected with the D71V DN variant, and embryos injected with the WT KCNJ2 construct. The normal pattern, at two different stages, is shown in the two left most columns. Examples of mispatterning of the markers are shown in the other columns. There was no consistent difference between the effects of the DN and the WT, indicating that the direction of change of Vmem does not prescribe a particular subset of defects.
	Chondrocranium and head cartilages of NF stage 46 X. laevis tadpole. A-C dorsal view, D-F ventral view. B and E, Alcian blue staining; C and F, after Reisoli et al. (2010). Note XAO terms synonyms used here: chondrocranium= head cartilages; ; ethmoid plate = planum trabeculare anticum; palatoquadrati= quadrate; subocular = subocular cartilage; Otic vesicle = Otocyst; genohyoideus (branchial arches) = pharyngeal arches.
	kcnj2 (potassium inwardly rectifying channel subfamily J member 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 17, anterio-dorsal view, dorsal up.
	kcnj2 (potassium inwardly rectifying channel subfamily J member 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 27, lateral view, anterior left, dorsal up.

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