The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation.

Genes implicated in translation control have been associated with autism spectrum disorders (ASDs). However, some important genetic causes of autism, including the 16p11.2 microdeletion, bear no obvious connection to translation. Here, we use proteomics, genetics, and translation assays in cultured cells and mouse brain to reveal altered translation mediated by loss of the kinase TAOK2 in 16p11.2 deletion models. We show that TAOK2 associates with the translational machinery and functions as a translational brake by phosphorylating eukaryotic elongation factor 2 (eEF2). Previously, all signal-mediated regulation of translation elongation via eEF2 phosphorylation was believed to be mediated by a single kinase, eEF2K. However, we show that TAOK2 can directly phosphorylate eEF2 on the same regulatory site, but functions independently of eEF2K signaling. Collectively, our results reveal an eEF2K-independent signaling pathway for control of translation elongation and suggest altered translation as a molecular component in the etiology of some forms of ASD.

Handedness and effector strength modulate a compatibility effect between stimulus size and response position with manual and vocal responses.

Humans respond more quickly with the left hand to a small stimulus, and with the right hand to a large stimulus, as compared to the reverse mapping (spatial-size association of response codes [SSARC] effect). We investigated the hypothesis that strength differences between the hands contribute to the origin of this effect. Therefore, 80 left-handers and 80 right-handers participated in two experiments. In Experiment 1, participants performed a manual choice-response task in which we manipulated the mapping between physical stimulus size and responding hand. In addition, we measured the strengths of participants' left and right effectors (i.e., finger, hand, and arm). In Experiment 2, we measured the SSARC effect in vocal responses of the same sample. There were four main results. First, participants' dominant effectors were stronger than their nondominant effectors. Second, the SSARC effect occurred in manual and vocal responses with similar size. Third, in both modalities, the SSARC effect was larger in right-handers than in left-handers. Finally, strength differences between effectors (fingers and hands) correlated with the size of the SSARC effect. In sum, results support the hypothesis that functional differences between the hands contribute to the origin of the SSARC effect. In addition, the results suggest that size-space associations have generalized across motor systems, and formed a modality-independent association. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The reciprocity of spatial-numerical associations of vocal response codes depends on stimulus mode.

Individuals make faster left responses to small/er numbers and faster right responses to large/r numbers than vice versa. This "spatial-numerical association of response codes" (SNARC) effect represents evidence for an overlap between the cognitive representations of number and space. Theories of the SNARC effect differ in whether they predict bidirectional S-R associations between number and space or not. We investigated the reciprocity of S-R priming effects between number and location in three experiments with vocal responses. In Experiments 1 and 2, participants completed a number-location task, with digits as stimuli and location words as responses, and a location-number task, with physical locations as stimuli and number words as responses. In addition, we varied the S-R mapping in each task. Results revealed a strong SNARC effect in the number-location task, but no reciprocal SNARC effect in the location-number task. In Experiment 3, we replaced physical location stimuli with location words and digit stimuli with number words. Results revealed a regular and a reciprocal SNARC effect of similar size. Reciprocal SNARC effects thus seem to emerge with verbal location stimuli and vocal responses, but not with physical location stimuli and vocal responses. The S-R associations underlying the SNARC effect with vocal responses thus appear bidirectional and symmetrical for some combinations of stimulus and response sets, but not for others. This has implications for theoretical accounts of the SNARC effect which need to explain how stimulus mode affects the emergence of reciprocal but not regular SNARC effects.

Protocol for differential multi-omic analyses of distinct cell types in the mouse cerebral cortex.

Here, we present a protocol for differential multi-omic analyses of distinct cell types in the developing mouse cerebral cortex. We describe steps for in utero electroporation, subsequent flow-cytometry-based isolation of developing mouse cortical cells, bulk RNA sequencing or quantitative liquid chromatography-tandem mass spectrometry, and bioinformatic analyses. This protocol can be applied to compare the proteomes and transcriptomes of developing mouse cortical cell populations after various manipulations (e.g., epigenetic). For complete details on the use and execution of this protocol, please refer to Meka et al. (2022).1.

Exploring the response code in a compatibility effect between physical size and left/right responses: The hand is more important than location.

The spatial-size association of response codes (SSARC) effect refers to the finding of better performance with the left hand to small stimuli and with the right hand to large stimuli, as compared to the reverse mapping. In the present study, we investigated which response coding is responsible for the emergence of the SSARC effect. We observed a SSARC effect only with response selection between hands but not between fingers of one hand, indicating that the responses are coded relative to the body midline. Furthermore, we observed a SSARC effect with parallel arms but not with crossed arms, suggesting that both the anatomical side of the effector and its external spatial position contribute to the response code. However, using a reaching task as compared to keypresses, the SSARC effect followed the arms, suggesting that the crucial spatial response code refers more strongly to the anatomical side of the effector rather than to the external spatial response position. These findings document a strong influence of anatomically- or body-based coding on the SSARC effect, are at odds with the proposition of a generalized magnitude system that utilizes a common, external spatial metric, and point toward a categorical nature of response codes underlying the SSARC effect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations between physical size and space are strongly asymmetrical.

The spatial-size association of response codes (SSARC) effect describes the phenomenon that left responses are faster and more accurate to small stimuli whereas right responses are faster and more accurate to large stimuli, as compared to the opposite mapping. The effect indicates associations between the mental representations of physical size and space. Importantly, the theoretical accounts of SSARC effects make different predictions about the reciprocity and/or symmetry of spatial-size associations. To investigate the reciprocity of SSARC effects, we compared compatibility effects in two verbal choice-response tasks: a size-location (typical SSARC) task and a location-size (reciprocal SSARC) task. In the size-location task, participants responded verbally to a small/large stimulus by saying "left"/"right". In the location-size task, participants responded verbally to a left-/right-side stimulus by saying "small"/"large". Participants completed both tasks with a compatible (small-left, large-right; left-small, right-large) and an incompatible (small-right, large-left; left-large, right-small) mapping. A regular SSARC effect emerged in the size-location task. However, no reciprocal SSARC effect emerged in the location-size task if outliers were excluded. If outliers were not excluded, small reciprocal SSARC effects occurred. Associations underlying the SSARC effect are thus strongly asymmetrical: Physical (stimulus) size can prime spatial responses much more strongly than spatial (stimulus) position can prime size-related responses. The finding of asymmetrical associations between size and space is in line with some theoretical accounts of the SSARC effect but at odds with others.

Spatial-numerical associations of manual response codes are strongly asymmetrical.

The spatial-numerical association of response codes (SNARC) effect denotes the observation that humans respond faster and more accurately with a left-side response to smaller numbers and a right-side response to larger numbers, as compared to the opposite mapping. Existing accounts, such as the mental number line hypothesis or the polarity correspondence principle, differ in whether they assume symmetrical associations between numerical and spatial stimulus and response codes or not. In two experiments, we investigated the reciprocity of the SNARC effect in manual choice-response tasks with two conditions. In the number-location task, participants pressed a left or right key to a number stimulus (dots in Experiment 1, digits in Experiment 2). In the location-number task, participants made one or two consecutive keypresses with one hand to a left- or right-side stimulus. Both tasks were performed with a compatible (one-left, two-right; left-one, right-two) and an incompatible (one-right, two-left; left-two, right-one) mapping. In both experiments, results showed a strong compatibility effect in the number-location task, reflecting the typical SNARC effect. In contrast, in both experiments, there was no mapping effect in the location-number task when outliers were excluded. However, when outliers were not excluded, small reciprocal SNARC effects occurred in Experiment 2. Together, the findings suggest that priming of spatial responses by numerical stimuli is much stronger than priming of numerical responses by spatial stimuli. The results are consistent with some accounts of the SNARC effect (e.g., the mental number line hypothesis), but not with others (e.g., the polarity correspondence principle).

Ultrasound Description of Follicular Development in the Louisiana Pinesnake (Pituophis ruthveni, Stull 1929).

Accurate monitoring of reproductive activity is necessary for success of captive breeding and recovery of endangered species. Using ultrasonography, we aimed to describe the stages of follicle development of the endangered Louisiana pinesnake (Pituophis ruthveni). Ultrasound procedures were performed weekly for 11 females during the 2020 reproductive season by submerging the last half of an unanesthetized female in water and using a 3.0-10.0 MHz linear array transducer placed and moved along the gastrosteges to explore the whole reproductive tract. The presence of follicles, their size, echogenicity, and stage of development was assessed. We observed small, round, anechoic, linearly aligned previtellogenic follicles in the coelom at the beginning of the reproductive season and found that structures dramatically increased in size and shifted in echogenicity as follicles matured and developed before and after ovulation. We classified follicles according to ultrasonographic appearance into 7 different follicle categories: previtellogenic, early vitellogenic, vitellogenic, preovulatory, peri-ovulatory, post ovulatory, and shelled. Using ultrasound, we developed markers of progressive follicular maturation for the Louisiana pinesnake and identified signs of abnormal development and post ovulatory follicle reabsorption. Detailed description of follicular maturation will be useful to improve captive breeding successes, identify mechanisms of reproductive failure, and develop artificial insemination.

TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model.

The precise development of the neocortex is a prerequisite for higher cognitive and associative functions. Despite numerous advances that have been made in understanding neuronal differentiation and cortex development, our knowledge regarding the impact of specific genes associated with neurodevelopmental disorders on these processes is still limited. Here, we show that Taok2, which is encoded in humans within the autism spectrum disorder (ASD) susceptibility locus 16p11.2, is essential for neuronal migration. Overexpression of de novo mutations or rare variants from ASD patients disrupts neuronal migration in an isoform-specific manner. The mutated TAOK2α variants but not the TAOK2ß variants impaired neuronal migration. Moreover, the TAOK2α isoform colocalizes with microtubules. Consequently, neurons lacking Taok2 have unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1. Mice lacking Taok2 develop gross cortical and cortex layering abnormalities. Moreover, acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice, and the expression of a constitutively active form of JNK1 rescued these neuronal migration defects. Finally, we report that the brains of the Taok2 KO and 16p11.2 del Het mouse models show striking anatomical similarities and that the heterozygous 16p11.2 microdeletion mouse model displayed reduced levels of phosphorylated JNK1 and neuronal migration deficits, which were ameliorated upon the introduction of TAOK2α in cortical neurons and in the developing cortex of those mice. These results delineate the critical role of TAOK2 in cortical development and its contribution to neurodevelopmental disorders, including ASD.

The Nature of Associations between Physical Stimulus Size and Left-Right Response Codes.

In two-choice response tasks, participants respond faster and more accurate with the left hand to a small stimulus and with the right hand to a large stimulus as compared to the reverse assignment. This compatibility effect suggests the existence of associations between cognitive codes of physical stimulus size and cognitive codes of left/right responses. Here, we explore the nature of associations between stimulus-size codes and left/right response codes by using more levels of stimulus size than in our previous studies. For example, the strengths of the associations between stimulus-size codes and response codes might either change gradually when stimulus size changes, or the strength of associations might change in a more discrete fashion (i.e., associations switch at a particular size level). In Experiment 1, participants responded to stimulus color with a left/right keypress, and physical stimulus size had ten levels with 5 mm steps. Results showed correspondence effects for the smallest and the largest stimulus size only. In Experiment 2, physical stimulus size had six levels with 10 mm steps. Results showed (similar) correspondence effects for the smallest and some intermediate stimulus-size levels. In sum, the results point towards a discrete, or categorical, relationship between cognitive codes of stimulus size and left/right response codes. This pattern of results is consistent with an account of the correspondence effect in terms of the polarity correspondence principle.

Relative, not absolute, stimulus size is responsible for a correspondence effect between physical stimulus size and left/right responses.

Recent studies have demonstrated a novel compatibility (or correspondence) effect between physical stimulus size and horizontally aligned responses: Left-hand responses are shorter and more accurate to a small stimulus, compared to a large stimulus, whereas the opposite is true for right-hand responses. The present study investigated whether relative or absolute size is responsible for the effect. If relative size was important, a particular stimulus would elicit faster left-hand responses if the other stimuli in the set were larger, but the same stimulus would elicit a faster right-hand response if the other stimuli in the set were smaller. In terms of two-visual-systems theory, our study explores whether "vision for perception" (i.e., the ventral system) or "vision for action" (i.e., the dorsal system) dominates the processing of stimulus size in our task. In two experiments, participants performed a discrimination task in which they responded to stimulus color (Experiment 1) or to stimulus shape (Experiment 2) with their left/right hand. Stimulus size varied as an irrelevant stimulus feature, thus leading to corresponding (small-left; large-right) and non-corresponding (small-right; large-left) conditions. Moreover, a set of smaller stimuli and a set of larger stimuli, with both sets sharing an intermediately sized stimulus, were used in different conditions. The consistently significant two-way interaction between stimulus size and response location demonstrated the presence of the correspondence effect. The three-way interaction between stimulus size, response location, and stimulus set, however, was never significant. The results suggest that participants are inadvertently classifying stimuli according to relative size in a context-specific manner.

Pum2 and TDP-43 refine area-specific cytoarchitecture post-mitotically and modulate translation of Sox5, Bcl11b, and Rorb mRNAs in developing mouse neocortex.

In the neocortex, functionally distinct areas process specific types of information. Area identity is established by morphogens and transcriptional master regulators, but downstream mechanisms driving area-specific neuronal specification remain unclear. Here, we reveal a role for RNA-binding proteins in defining area-specific cytoarchitecture. Mice lacking Pum2 or overexpressing human TDP-43 show apparent 'motorization' of layers IV and V of primary somatosensory cortex (S1), characterized by dramatic expansion of cells co-expressing Sox5 and Bcl11b/Ctip2, a hallmark of subcerebral projection neurons, at the expense of cells expressing the layer IV neuronal marker Rorß. Moreover, retrograde labeling experiments with cholera toxin B in Pum2; Emx1-Cre and TDP43A315T mice revealed a corresponding increase in subcerebral connectivity of these neurons in S1. Intriguingly, other key features of somatosensory area identity are largely preserved, suggesting that Pum2 and TDP-43 may function in a downstream program, rather than controlling area identity per se. Transfection of primary neurons and in utero electroporation (IUE) suggest cell-autonomous and post-mitotic modulation of Sox5, Bcl11b/Ctip2, and Rorß levels. Mechanistically, we find that Pum2 and TDP-43 directly interact with and affect the translation of mRNAs encoding Sox5, Bcl11b/Ctip2, and Rorß. In contrast, effects on the levels of these mRNAs were not detectable in qRT-PCR or single-molecule fluorescent in situ hybridization assays, and we also did not detect effects on their splicing or polyadenylation patterns. Our results support the notion that post-transcriptional regulatory programs involving translational regulation and mediated by Pum2 and TDP-43 contribute to elaboration of area-specific neuronal identity and connectivity in the neocortex.

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity.

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.

An anti-narcolepsy drug reveals behavioral and fitness costs of extreme activity cycles in arctic-breeding songbirds.

Sleep loss impairs cognitive function, immunological responses and general well-being in humans. However, sleep requirements in mammals and birds vary dramatically. In circumpolar regions with continuous summer light, daily sleep duration is reduced, particularly in breeding birds. The effect of an anti-narcolepsy drug (modafinil) to putatively extend wakefulness was examined in two species of closely related arctic-breeding passerine birds: Lapland longspurs (Calcarius lapponicus) and snow buntings (Plectrophenax nivalis). Free-living adult males were implanted during the nestling phase on day 4 (D4; 4 days post-hatching) with osmotic pumps containing either vehicle or modafinil to extend the active period for 72 h. Nestlings were weighed on D2 and D7 to measure growth rates. Additionally, focal observations were conducted on D6. Male longspurs receiving modafinil made fewer feeding visits and spent less time at the nest but tended to spend more time near the nest than controls. We observed no change in longspur nestling growth rates, but fledging occurred significantly later when males received modafinil, suggesting a fitness cost. In contrast, modafinil had no measurable impact on male or female snow bunting behavior, nestling growth rates or time to fledging. We suggest male longspurs compromise and maintain vigilance at their nests in lieu of sleeping because of the increased predation risk that is characteristic of their tundra nesting habitat. Snow buntings are cavity nesters, and their nests do not require the same vigilance, allowing males to presumably rest following provisioning. These life-history differences between species highlight the role of predation risk in mediating behavioral modifications to prolonged wakefulness in arctic-breeding songbirds.

Oligodendrocyte precursor cell specification is regulated by bidirectional neural progenitor-endothelial cell crosstalk.

Neural-derived signals are crucial regulators of CNS vascularization. However, whether the vasculature responds to these signals by means of elongating and branching or in addition by building a feedback response to modulate neurodevelopmental processes remains unknown. In this study, we identified bidirectional crosstalk between the neural and the vascular compartment of the developing CNS required for oligodendrocyte precursor cell specification. Mechanistically, we show that neural progenitor cells (NPCs) express angiopoietin-1 (Ang1) and that this expression is regulated by Sonic hedgehog. We demonstrate that NPC-derived Ang1 signals to its receptor, Tie2, on endothelial cells to induce the production of transforming growth factor beta 1 (TGFß1). Endothelial-derived TGFß1, in turn, acts as an angiocrine molecule and signals back to NPCs to induce their commitment toward oligodendrocyte precursor cells. This work demonstrates a true bidirectional collaboration between NPCs and the vasculature as a critical regulator of oligodendrogenesis.

Conserved Tao Kinase Activity Regulates Dendritic Arborization, Cytoskeletal Dynamics, and Sensory Function in Drosophila.

Dendritic arborization is highly regulated and requires tight control of dendritic growth, branching, cytoskeletal dynamics, and ion channel expression to ensure proper function. Abnormal dendritic development can result in altered network connectivity, which has been linked to neurodevelopmental disorders, including autism spectrum disorders (ASDs). How neuronal growth control programs tune dendritic arborization to ensure function is still not fully understood. Using Drosophila dendritic arborization (da) neurons as a model, we identified the conserved Ste20-like kinase Tao as a negative regulator of dendritic arborization. We show that Tao kinase activity regulates cytoskeletal dynamics and sensory channel localization required for proper sensory function in both male and female flies. We further provide evidence for functional conservation of Tao kinase, showing that its ASD-linked human ortholog, Tao kinase 2 (Taok2), could replace Drosophila Tao and rescue dendritic branching, dynamic microtubule alterations, and behavioral defects. However, several ASD-linked Taok2 variants displayed impaired rescue activity, suggesting that Tao/Taok2 mutations can disrupt sensory neuron development and function. Consistently, we show that Tao kinase activity is required in developing and as well as adult stages for maintaining normal dendritic arborization and sensory function to regulate escape and social behavior. Our data suggest an important role for Tao kinase signaling in cytoskeletal organization to maintain proper dendritic arborization and sensory function, providing a strong link between developmental sensory aberrations and behavioral abnormalities relevant for Taok2-dependent ASDs.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are linked to abnormal dendritic arbors. However, the mechanisms of how dendritic arbors develop to promote functional and proper behavior are unclear. We identified Drosophila Tao kinase, the ortholog of the ASD risk gene Taok2, as a regulator of dendritic arborization in sensory neurons. We show that Tao kinase regulates cytoskeletal dynamics, controls sensory ion channel localization, and is required to maintain somatosensory function in vivo Interestingly, ASD-linked human Taok2 mutations rendered it nonfunctional, whereas its WT form could restore neuronal morphology and function in Drosophila lacking endogenous Tao. Our findings provide evidence for a conserved role of Tao kinase in dendritic development and function of sensory neurons, suggesting that aberrant sensory function might be a common feature of ASDs.

The Microtubule Severing Protein Katanin Regulates Proliferation of Neuronal Progenitors in Embryonic and Adult Neurogenesis.

Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.

Light at night disrupts diel patterns of cytokine gene expression and endocrine profiles in zebra finch (Taeniopygia guttata).

Increased exposure to light pollution perturbs physiological processes through misalignment of daily rhythms at the cellular and tissue levels. Effects of artificial light-at-night (ALAN) on diel properties of immunity are currently unknown. We therefore tested the effects of ALAN on diel patterns of cytokine gene expression, as well as key hormones involved with the regulation of immunity, in zebra finches (Taeniopygia guttata). Circulating melatonin and corticosterone, and mRNA expression levels of pro- (IL-1ß, IL-6) and anti-inflammatory (IL-10) cytokines were measured at six time points across 24-h day in brain (nidopallium, hippocampus, and hypothalamus) and peripheral tissues (liver, spleen, and fat) of zebra finches exposed to 12 h light:12 h darkness (LD), dim light-at-night (DLAN) or constant bright light (LLbright). Melatonin and corticosterone concentrations were significantly rhythmic under LD, but not under LLbright and DLAN. Genes coding for cytokines showed tissue-specific diurnal rhythms under LD and were lost with exposure to LLbright, except IL-6 in hypothalamus and liver. In comparison to LLbright, effects of DLAN were less adverse with persistence of some diurnal rhythms, albeit with significant waveform alterations. These results underscore the circadian regulation of biosynthesis of immune effectors and imply the susceptibility of daily immune and endocrine patterns to ALAN.

Radial somatic F-actin organization affects growth cone dynamics during early neuronal development.

The centrosome is thought to be the major neuronal microtubule-organizing center (MTOC) in early neuronal development, producing microtubules with a radial organization. In addition, albeit in vitro, recent work showed that isolated centrosomes could serve as an actin-organizing center, raising the possibility that neuronal development may, in addition, require a centrosome-based actin radial organization. Here, we report, using super-resolution microscopy and live-cell imaging of cultured rodent neurons, F-actin organization around the centrosome with dynamic F-actin aster-like structures with F-actin fibers extending and retracting actively. Photoactivation/photoconversion experiments and molecular manipulations of F-actin stability reveal a robust flux of somatic F-actin toward the cell periphery. Finally, we show that somatic F-actin intermingles with centrosomal PCM-1 (pericentriolar material 1 protein) satellites. Knockdown of PCM-1 and disruption of centrosomal activity not only affect F-actin dynamics near the centrosome but also in distal growth cones. Collectively, the data show a radial F-actin organization during early neuronal development, which might be a cellular mechanism for providing peripheral regions with a fast and continuous source of actin polymers, hence sustaining initial neuronal development.

Maintenance of cell type-specific connectivity and circuit function requires Tao kinase.

Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in the Drosophila nociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth.