<i>skn-1</i> is expressed in AIY neurons and regulates their functions.

<p>(A) Schematic of the neuronal circuits of <i>C</i>. <i>elegans</i> chemoattractive and thermotactic behaviors. Green triangles represent sensory neurons and blue hexagons command interneurons. Arrows indicate direct interactions, and their thickness is proportional to the frequency of synaptic contacts between the neurons (Adapted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176798#pone.0176798.ref036" target="_blank">36</a>]). T, thermophilic; C, cryophilic.(Adapted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176798#pone.0176798.ref041" target="_blank">41</a>]). (B) Population thermotaxis experiments were performed using a radial thermal gradient. After 60 minutes the position of the worms was scored and the percentages of worms in the colder (Zone 1) and warmer (Zone 2) regions determined. N2 animals moved toward the region of the plate closer to their previous cultivation temperature (23°C), while both <i>skn-1</i> null strains <i>zu135</i> and <i>zu67</i> showed a cryophilic phenotype similar to <i>ttx-3</i> (AIY) null worms. (C) Representative 3D reconstruction of confocal sections through the head region of double transgenic <i>wglS342;otlS133</i> worms is shown. The <i>skn-1</i>:<i>EGFP</i> reporter (green), containing the entire <i>skn-1</i> gene, is highly expressed in neurons in the head ganglia, and colocalizes with the AIY-specific marker <i>ttx3</i>:RFP (Red). Arrows point at AIY. Scale bar 10 μm. (D) Relative mRNA levels of the AIY cell fate specification homeobox genes <i>ttx-3</i> and <i>ceh-23</i>, and their targets <i>ser-2a</i>, <i>ser-2b</i>, <i>sra-11</i>, <i>kal-1</i> and <i>hen-1</i> in N2 and <i>skn-1</i> null worms. (E) Representative 3D reconstructions showing the expression of the transcriptional reporter <i>ser2</i>:<i>prom1</i>:<i>EGFP</i> in the head region of N2 and <i>skn-1(zu135)</i> null worms. Data are mean and S.E.M. of 3–5 experiments. *p<0.05; **p<0.01; ***p<0.001 versus N2 (Student’s <i>t</i>-test).</p

<i>skn-1</i> is required for interneuron sensory integration and foraging behavior in <i>Caenorhabditis elegans</i>

<div><p>Nrf2/<i>skn-1</i>, a transcription factor known to mediate adaptive responses of cells to stress, also regulates energy metabolism in response to changes in nutrient availability. The ability to locate food sources depends upon chemosensation. Here we show that Nrf2/<i>skn-1</i> is expressed in olfactory interneurons, and is required for proper integration of multiple food-related sensory cues in <i>Caenorhabditis elegans</i>. Compared to wild type worms, <i>skn-1</i> mutants fail to perceive that food density is limiting, and display altered chemo- and thermotactic responses. These behavioral deficits are associated with aberrant AIY interneuron morphology and migration in <i>skn-1</i> mutants. Both <i>skn-1</i>-dependent AIY autonomous and non-autonomous mechanisms regulate the neural circuitry underlying multisensory integration of environmental cues related to energy acquisition.</p></div

Nrf2 is highly expressed in olfactory bulb interneurons.

<p>(A) Representative immunoblots and quantification of Nrf2 protein levels in adult murine brain (n = 4). Values were normalized by GAPDH and expressed as mean percentage (and S.E.M.) compared to olfactory bulb (OB). Cx, cortex; Hp, hippocampus; Cb, cerebellum; Me, medulla. (B) Schematic showing the rostral migratory stream (RMS), the route followed by neuroblasts originating in the sub ventricular zone (SVZ) to reach the olfactory bulb (OB). Immunohistochemistry showing the expression of Nrf2 in the RMS at low magnification (left) and high magnification (right). The boxed area indicates the regions shown in the immunostaining. (C) Immunohistochemistry showing the distribution of Nrf2 in the various regions of the olfactory bulb (upper panel). GCL: granule cell layer; MCL: mitral cell layer; EPL: external plexiform layer; GL: glomerular layer. The higher magnification panels show Nrf2 subcellular localization in mitral cells (MCL) and granule cells (GCL).</p

<i>skn-1</i> regulates AIY neuron morphology and food-seeking behavior by cell-autonomous and non-autonomous mechanisms.

<p>(A) Schematic depiction, representative images, and quantification of the neuroanatomical defects observed in <i>skn-1(zu135)</i> worms. Wild type morphology is shown in black, while aberrant branches from the axon or cell body are depicted in red. Also shown are examples of premature stops, and axon misrouting. (B) Schematic depiction and representative images of the AIY position relative to the pharynx grinder in N2 (black line) and <i>skn-1(zu135)</i> worms (red line). a, distance between grinder and the AIY axon fasciculation at the nerve ring; b, distance between the grinder and AIY cell body. Quantification of the AIY migratory defects in the indicated worm strains. AIY-specific expression of <i>skn-1b</i> has no effect on migration (B), and food-leaving behavior (C) (OP50 = 0.033x). Pan-neuronal expression of <i>skn-1b</i> significantly decreases AIY migratory defects (B) and partially rescues the food-leaving behavior (D). Data are mean and S.E.M. of 3–7 experiments. ***p<0.001 versus N2; ###p<0.001 versus <i>skn-1</i> (zu135) (Student’s <i>t</i>-test).</p