Cell-type-specific promoters for C. elegans glia

Figures & data

Figure 1. Schematic of a C. elegans sense organ in thehead. A typical C. elegans sense organ contains one or more sensory neurons (red) and two glial cells, called the sheath (orange) and socket (green). Most sensory neurons extend a ciliated dendritic ending through a tube-shaped pore formed by the sheath and socket glia. The socket glia secretes cuticle (gray) that forms an open pore through which chemosensory dendrite endings protrude, as shown, or a closed sheet into which mechanosensory dendrite endings are embedded (not shown). Tight junctions (yellow) are present between the neuron and sheath glia, the sheath and socket glia, and the socket glia and skin. See online version for color figure.

Table 1. Glial promoters used in the literature.

AMsh or PHsh
F16F9.3	2 kb promoter	Bacaj et al. (2008); Braunreiter, Hamlin, & Lyman-Gingerich (2014); Heiman & Shaham (2009); Low et al. (2019); Mizeracka, Rogers, Shaham, Bulyk, & Heiman (2019); Oikonomou et al. (2011); Procko et al. (2012, 2011); Singhvi et al. (2016); Wallace et al. (2016); Yip & Heiman (2018)
vap-1 (developmentally regulated)	2797 bp or 5205 bp promoter	Bacaj et al. (2008); Ding et al. (2015); Oikonomou et al. (2011); Perens & Shaham (2005); Procko et al. (2011); Wallace et al. (2016); Wang et al. (2017) Wang, D'Urso, & Bianchi (2012, 2008)
T02B11.3	2.5 kb promoter	Bacaj et al. (2008); Grant, Matthewman, & Bianchi (2015); Mizeracka et al. (2019); Oikonomou, Perens, Lu, & Shaham (2012) Oikonomou et al. (2011); Procko et al. (2011); Wang et al. (2017, 2008)
fig-1	2.2 kb promoter	Bacaj et al. (2008); Fenk & de Bono (2015); Kage-Nakadai et al. (2016); Wallace et al. (2016); Yoshida et al. (2016)
ver-1 (thermo- and dauer-regulated)	2110 bp promoter	Popovici et al. (2002); Procko et al. (2012, 2011); Yoshida et al. (2016)
F53F4.13	650 bp promoter	Bacaj et al. (2008); Mizeracka et al. (2019); Singhvi et al. (2016)
F11C7.2	350 bp promoter	Bacaj et al. (2008); Wallace et al. (2016)
hmit-1.2 (osmo-regulated)	979 bp promoter	Kage-Nakadai et al. (2016, 2011)
lit-1	2.5 kb promoter	Oikonomou et al. (2011); Wallace et al. (2016)
grl-28	2553 bp promoter	Hao et al. (2006)
acd-1	2550 bp promoter, plus coding sequences	Wang et al. (2008)
F52E1.2	3.3 kb promoter	Ohkura & Bürglin (2011)
hmit-1.3	4883 bp promoter	Kage-Nakadai et al. (2011)
F58F9.6	4 kb promoter	Procko et al. (2012)
K02E11.4	800 bp promoter	Wallace et al. (2016)
R11D1.3	900 bp promoter	Wallace et al. (2016)
bgnt-1.1	recombineered fosmid	Timbers et al. (2016)
AMso or PHso
itr-1	2.3 kb promoter (from between exon 1 and exon 2)	Gower et al. (2001); Han et al. (2013); Heiman & Shaham (2009); Mizeracka et al. (2019); Sammut et al. (2015); Tucker, Sieber, Morphew, & Han (2005); Wang et al. (2017)
grl-2	2981 bp promoter	Hao et al. (2006); Hunt-Newbury et al. (2007); Low et al. (2019); Mizeracka et al. (2019); Molina-García et al. (2018); Sammut et al. (2015)
lin-48	6.8 kb promoter	Johnson et al. (2001); Mizeracka et al. (2019); Molina-García et al. (2018)
grd-15	840 bp promoter	Hunt-Newbury et al. (2007); Timbers et al. (2016)
unc-53	3.4 kb promoter (from exon 8 to exon 13)	Stringham, Pujol, Vandekerckhove, & Bogaert (2002); Tucker et al. (2005)
alr-1	1 kb promoter	Tucker et al. (2005)
abt-4	2472 bp promoter	Hunt-Newbury et al. (2007)
grl-6	939 bp promoter	Hunt-Newbury et al. (2007)
srp-2	2833 bp promoter	Hunt-Newbury et al. (2007)
Combinations of AMsh, AMso, PHsh, and PHso
daf-6	3 kb promoter	Kage-Nakadai et al. (2016); Moussaif & Sze (2009); Ohkura & Bürglin (2011); Perens & Shaham (2005); Wallace et al. (2016)
ztf-16	2.1 kb enhancer (from 4637 to 2536 bp upstream of ATG)	Procko et al. (2012); Sammut et al. (2015)
ttx-1	3.5 kb enhancer (from 11 to 7.5 kb upstream of ATG)	Procko et al. (2011)
CEPsh
hlh-17	2.5 kb promoter or 1.9 kb promoter	Cianciulli et al. (2019); Colón-Ramos et al. (2007); Gibson et al. (2018); Ji et al. (2019); Katz, Corson, Iwanir, Biron, & Shaham (2018); McMiller & Johnson (2005); Mizeracka et al. (2019); Rapti et al. (2017); Sammut et al. (2015); Shao et al. (2013); Stout & Parpura (2011); Yoshida et al. (2016); Yoshimura et al. (2008)
swip-10	1.5 kb enhancer (from fifth intron, 1013 to 2504 bp downstream of ATG)	Hardaway et al. (2015)
twk-16	3412 bp promoter	Cianciulli et al. (2019)
ILso
grl-18	2968 or 2962 bp promoter	Cebul et al. (2020); Hao et al. (2006); Mizeracka et al. (2019)
Combinations of ILsh, ILso, OLsh, and OLso
itx-1	2977 bp promoter or 1.8 kb promoter	Haklai-Topper et al. (2011); Han et al. (2013); McQuary et al. (2016); Sammut et al. (2015)
delm-1	2 kb promoter	Han et al. (2013)
delm-2	1.4 kb promoter	Han et al. (2013)
Most (or many) glia
ptr-10	300 bp promoter	Gibson et al. (2018); Hardaway et al. (2015); Katz et al. (2018); Oikonomou et al. (2011); Rapti et al. (2017); Sammut et al. (2015); Wallace et al. (2016); Yin et al. (2017); Yoshida et al. (2016); Yoshimura et al. (2008)
mir-228	2.2 kb promoter	Molina-García et al. (2018); Pierce et al. (2008); Rapti et al. (2017); Wallace et al. (2016); Wang et al. (2017); Yin et al. (2017)
kcc-3	3.9 kb promoter and 2.2 kb downstream sequences	McQuary et al. (2016); Singhvi et al. (2016); Tanis, Bellemer, Moresco, Forbush, & Koelle (2009); Yoshida et al. (2016)
pros-1	recombineered fosmid or 9 kb promoter	Kage-Nakadai et al. (2016); Wallace et al. (2016)
Unidentified combinations of glia
grd-8	905 bp promoter	Hao et al. (2006)
grd-16	2866 bp promoter	Hao et al. (2006)
grl-1	287 bp promoter	Hao et al. (2006)
grl-6	940 bp promoter	Hao et al. (2006)
grl-8	2893 bp promoter	Hao et al. (2006)
grl-12	2989 bp promoter	Hao et al. (2006)
grl-13	2843 bp promoter	Hao et al. (2006)
grl-17	2869 bp promoter	Hao et al. (2006)
grl-29	1893 bp promoter	Hao et al. (2006)
rgba-1	2.1 kb promoter	Yin et al. (2017)
argk-1	1.2 kb promoter	McQuary et al. (2016)

Promoters with glial-specific expression were identified in the literature. Within each group, promoters are listed in order from most to least frequently used.

Figure 2. Cell-type-specific promoters for sheath and socket glia. (A) Merged brightfield images and pseudo-colored fluorescence projections of animals expressing fluorescent proteins under control of promoters selected for brightness, specificity, and consistency. F16F9.3 (pink, AMsh and PHsh); F11C7.2 (purple, AMsh only); hlh-17 (orange, CEPsh); grl-2 (blue, AMso, PHso1, and PHso2; also expressed in excretory duct and pore cells, white arrow); grl-18 (green, ILso). (B) Magnified images of AMsh (pink, F16F9.3), CEPsh (orange, hlh-17), and AMso (blue, grl-2), showing that their brightness is sufficient to resolve fine structural details including the tube-like pores of the AMsh and AMso glia and the branch-like posterior processes of the CEPsh glia. (C) Head of an animal expressing grl-18pro:GFP (green, ILso glia) and klp-6pro:mCherry (red, IL2 neurons), demonstrating that the grl-18 promoter labels the six ILso glia, identified by their processes which each form a pore for the ciliated dendritic ending of an IL2 sensory neuron. See online version for color figure.

Table 2. Recommended cell-type-specific glial promoters.

Gene	Promoter (bp)	Glia marked	Other cells marked	References
F16F9.3	2000	AMsh, PHsh	none	Bacaj et al. (2008)
F11C7.2	350	AMsh	none	Bacaj et al. (2008)
hlh-17	2500	CEPsh	none	McMiller & Johnson (2005); Yoshimura et al. (2008)
grl-2	2981	AMso, PHso1, PHso2	excretory duct, pore	Hao et al. (2006)
grl-18	2962	ILso	vulval epithelial cells	Cebul et al. (2020); Hao et al. (2006)
mir-228	2200	all (or nearly all) glia	seam cells, excretory cell	Pierce et al. (2008)

For each marker, the promoter column indicates the size (bp) of the genomic DNA fragment that is taken directly upstream of the gene translation start site, except hlh-17 for which the 3′ end of the promoter fragment is 118 bp upstream of the translation start site.

Figure 3. Promoters expressed in combinations of glia. (A) Images of head expression of GFP under control of the pan-glial promoter mir-228 and the variable glial promoters delm-1 and itx-1. (B) Quantification of the number of GFP-expressing glia observed with delm-1 (n = 20) and itx-1 (n = 24) extrachromosomal reporters. Error bars indicate standard deviation. p < 0.0001, unpaired t-test with Welch’s correction. (C) Merged brightfield and fluorescence projections of a whole animal expressing pan-glial mir-228pro:GFP.

Figure 4. Plasticity in glial gene expression. (A) vap-1pro:RFP expression in AMsh glia in animals at the third larval (L3), fourth larval (L4), and 1-day adult life stages, showing developmental regulation of gene expression. (B) ver-1pro:GFP expression in AMsh glia in L4 animals grown at 15 °C, 20 °C, or 25 °C, showing thermoregulation of gene expression as previously described (Procko et al., 2012, 2011). (C) Quantification of vap-1pro:RFP fluorescence in AMsh glia from second larval (L2) stage to 1-day adults and in dyf-7(ns119) L4 and adult animals, showing that sensory defects alter gene expression. n = 15–16 per group. p < 0.05, dyf-7 L4 vs dyf-7 adults; p < 0.0001, dyf-7 adults vs wild-type adults; unpaired t-test with Welch’s correction (D) Quantification of ver-1pro:GFP fluorescence in the AMsh glia in L4 animals from 15 °C to 25 °C. n = 21–23 per group. p < 0.05, 20 °C vs 15 °C; p < 0.0001, 20 °C vs 25 °C; Brown-Forsyth and Welch one-way ANOVA with Dunnett’s multiple comparisons test.

Figure 5. Prospective identification of novel cell-type-specific promoters for ILso glia. (A) Cell cluster plots illustrating the expression of grl-18 and col-53 in embryonic glia and excretory cells from Packer et al., 2019. Each point represents an individual cell. The color indicates the relative expression level of each gene. For grl-18, low expression is black and high expression is red. For col-53, low is blue and high is green/yellow. Gray indicates no detected transcripts for the gene of interest. Inset box, the cell cluster predicted to include ILso glia. Cell cluster plot for col-177 is in Supplementary Figure S1(A). (B, C) Merged brightfield and fluorescence images of an animal expressing grl-18pro:mApple together with (B) col-53pro:GFP or (C) col-177pro:GFP, showing that these markers are expressed in the same cells. col-177 is also faintly expressed in cells with a glial morphology, tentatively identified as OLL socket glia in the head (arrowheads, see Supplementary Figure S1(B)) and ADE and PDE socket glia in the body. See online version for color figure.

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