De novo mutations in CHD8 are strongly associated with autism spectrum disorder (ASD), however the basic biology of CHD8 remains poor understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of Chd8 expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the neurodevelopmental role of Chd8.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Animals find mates and food, and avoid predators, by navigating to regions within a favorable range of available sensory cues. How are these ranges set and recognized? Here we show that male Caenorhabditis elegans exhibit strong concentration preferences for sex-specific small molecule cues secreted by hermaphrodites, and that these preferences emerge from the collective dynamics of a single male-specific class of neurons, the cephalic sensory neurons (CEMs). Within a single worm, CEM responses are dissimilar, not determined by anatomical classification and can be excitatory or inhibitory. Response kinetics vary by concentration, suggesting a mechanism for establishing preferences. CEM responses are enhanced in the absence of synaptic transmission, and worms with only one intact CEM show nonpreferential attraction to all concentrations of ascaroside for which CEM is the primary sensor, suggesting that synaptic modulation of CEM responses is necessary for establishing preferences. A heterogeneous concentrationdependent sensory representation thus appears to allow a single neural class to set behavioral preferences and recognize ranges of sensory cues.T he chemical senses of taste and smell are an important source of sensory input for organisms from worms to humans, and elements of the olfactory system are evolutionarily conserved across metazoa (1, 2). The neural mechanisms of olfactory processing are a subject of active research (3), and much is known about the encoding of odor identity and concentration (4-6). However, the issue of ranges of favorable odor concentrations has been less studied. A reasonable general hypothesis is that physical sensory limitations set perceptual boundaries, limiting the range of an animal to respond favorably. However, there are instances where differences in odor concentrations can have different meanings: For example, both male and female rodents produce the same pheromone at different concentrations (7), and so males need to be able to distinguish between low and high concentrations. Similarly, a very high concentration might signal an adverse environment with overcrowding, in which case the animal is better off looking elsewhere. In such cases, the concentration preferences of the animals are tuned to some optimal value that has a higher probability of a successful outcome. Here, we show that Caenorhabditis elegans exhibits a striking tuning of pheromone concentration preferences, and that this concentration tuning is actively built and maintained by a single class of male-specific neurons, the cephalic sensory neurons (CEMs).The nervous system of C. elegans is famously compact, with 302 hermaphrodite neurons grouped into 118 classes based on morphology and connectivity (8), and 385 male neurons (9-11). Some classes of neurons are sex-specific (Fig. 1A). Members of a class are typically distinguished from each other by their relative anatomical position, such as left/right and dorsal/ventral. Although initially it was thought that members of a class were functionally similar, ...