Guidance Receptor Degradation Is Required for Neuronal Connectivity in the Drosophila Nervous System

During Drosophila brain development, a neuron-specific endolysosomal degradation pathway provides a mechanism for continuous guidance receptor turnover and proper connectivity

Prosodic focus marking in Seoul Korean-speaking children: the use of prosodic phrasing

IntroductionProsodic focus marking in Seoul Korean is known to be achieved primarily through prosodic phrasing, different from the use of prosody for this purpose in many other languages. This study investigates how children use prosodic phrasing for focus-marking purposes in Seoul Korean, compared to adults.MethodsUsing a picture-matching game, we elicited semi-spontaneous production of SOV sentences in various focus conditions from monolingual Seoul Korean-speaking children aged 4 to 11 years.ResultsWe found that the children varied prosodic boundaries to distinguish narrow focus from pre-focus and broad focus in a largely adult-like manner at the age of 4 to 5; at this age, they did not distinguish narrow focus from post-focus or contrastive focus using prosodic boundaries, similar to the adults. Their use of the prosodic boundaries in distinguishing the focus conditions was not fully adult-like in terms of frequency until the age of 10 to 11.DiscussionIn conjunction with the findings of previous studies on the acquisition of focus marking in Germanic languages, performed using a similar experimental method, our findings suggest that Seoul Korean-speaking children acquire the use of prosodic phrasing earlier than Dutch-speaking children acquiring the use of pitch accent but slightly later than Stockholm Swedish-speaking children acquiring the use of a prominence-marking high tone. These findings imply that the rate of focus-marking acquisition depends on the transparency of the form-meaning mapping between the phonological cue and focus

Characterizing the Molecular Mechanisms of Axon Guidance: Activation and Regulation of the Axon Guidance Receptor Plexin A

Neuronal connectivity is precisely determined by axonal pathfinding during development. The navigating axons detect attractive and repulsive environmental cues by axon guidance receptors. However, the biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood. Semaphorins are the largest family of axon guidance cues and utilize Plexin receptors to exert repulsive effects on axon extension. The intracellular region of Plexins contains a Ras GTPase activating protein (GAP) domain, which is necessary for repulsive guidance effects. Previous studies suggest that activation of Plexin RasGAP requires interactions with both Semaphorin at the extracellular region and a Rho-family GTPase at the Rho family GTPase-binding domain (RBD). Interestingly, Semaphorin repulsion can be rapidly "turned-off" by other distinct cues and signaling cascades. However, the molecular mechanisms to activate or modulate Plexin RasGAP remain unclear. First, to further understand how the Plexin RasGAP is activated, I collaborated with the Zhang lab, and following determination of the crystal structure of the intracellular region of Plexin, I examined the roles of residues interfacing with the RasGAP domain using functional mutagenesis in the Drosophila model system. Our results demonstrate that Plexin exhibits an auto-inhibited conformation, and suggest that interaction among the previously uncharacterized juxtamembrane segment, the RBD, and the RasGAP domain is critical for Plexin RasGAP activation. Second, to better understand how Semaphorin/Plexin signaling is modulated, I characterized the results of a large-scale screen to look for proteins interacting with the cytoplasmic portion of Plexin and identified the phosphoserine binding protein 14-3-3epsilon as a specific Plexin-interacting protein. My results reveal that 14-3-3epsilon is specifically required for axon guidance during development. Moreover, Protein kinase A is found to phosphorylate Plexin in the RasGAP domain and mediates the 14-3-3epsilon interaction. Plexin-14-3-3epsilon interactions prevent Plexin from interacting with its Ras-family GTPase substrate, which effectively switches Plexin-mediated axonal repulsion to Integrin-mediated adhesion. These findings uncover both a new molecular integration point between important axon guidance signaling pathways and a biochemical logic by which this guidance information is coalesced to steer the growing axon. Therefore, these new observations on activating and silencing specific signals that are repulsive to axon growth also illuminate new approaches to neutralize axonal growth inhibition and encourage axon regeneration

Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration

Plexin cell surface receptors bind to semaphorin ligands and transduce signals for regulating neuronal axon guidance. The intracellular region of plexins is essential for signaling and contains a R-Ras/M-Ras GTPase activating protein (GAP) domain that is divided into two segments by a Rho GTPase-binding domain (RBD). The regulation mechanisms for plexin remain elusive, although it is known that activation requires both binding of semaphorin to the extracellular region and a Rho-family GTPase (Rac1 or Rnd1) to the RBD. Here we report the crystal structure of the plexin A3 intracellular region. The structure shows that the N- and C-terminal portions of the GAP homologous regions together form a GAP domain with an overall fold similar to other Ras GAPs. However, the plexin GAP domain adopts a closed conformation and cannot accommodate R-Ras/M-Ras in its substrate-binding site, providing a structural basis for the autoinhibited state of plexins. A comparison with the plexin B1 RBD/Rnd1 complex structure suggests that Rnd1 binding alone does not induce a conformational change in plexin, explaining the requirement of both semaphorin and a Rho GTPase for activation. The structure also identifies an N-terminal segment that is important for regulation. Both the N-terminal segment and the RBD make extensive interactions with the GAP domain, suggesting the presence of an allosteric network connecting these three domains that integrates semaphorin and Rho GTPase signals to activate the GAP. The importance of these interactions in plexin signaling is shown by both cell-based and in vivo axon guidance assays

Hypothalamic neurons that mirror aggression

Social interactions require awareness and understanding of the behavior of others. Mirror neurons, cells representing an action by self and others, have been proposed to be integral to the cognitive substrates that enable such awareness and understanding. Mirror neurons of the primate neocortex represent skilled motor tasks, but it is unclear if they are critical for the actions they embody, enable social behaviors, or exist in non-cortical regions. We demonstrate that the activity of individual VMHvlPR neurons in the mouse hypothalamus represents aggression performed by self and others. We used a genetically encoded mirror-TRAP strategy to functionally interrogate these aggression-mirroring neurons. We find that their activity is essential for fighting and that forced activation of these cells triggers aggressive displays by mice, even toward their mirror image. Together, we have discovered a mirroring center in an evolutionarily ancient region that provides a subcortical cognitive substrate essential for a social behavior

Developmental pathway of phonetic fine-tuning of phonological contrast in reference to information structure: The case of three-way contrastive stops in Korean.

This study investigates the acquisition of three-way stop contrast (lenis, aspirated, fortis) in Korean and phonetic modulation of the phonological contrast driven by information structure. VOT and F0 of the stops produced by children (4-5, 7-8, 10-11 year-olds) and adults in broad, narrow, and contrastive focus conditions were measured. Results indicated that only the 7-8 year-olds showed the three-way distinction using VOT under (phonemic) contrastive focus, while the other two children groups and adults did not. As for F0, adults made a three-way distinction using F0 in all focus conditions, while the 7-8 and the 10-11 year-olds did so only under limited focus conditions. The 4-5 year-olds did not show the three-way distinction in any focus condition. The results suggest that children build up their phonological awareness and fine-tune phonetic realization in their developmental pathway in conjunction with different functions of information structur

Developmental pathway of phonetic fine-tuning of phonological contrast in reference to information structure: The case of three-way contrastive stops in Korean.

This study investigates the acquisition of three-way stop contrast (lenis, aspirated, fortis) in Korean and phonetic modulation of the phonological contrast driven by information structure. VOT and F0 of the stops produced by children (4-5, 7-8, 10-11 year-olds) and adults in broad, narrow, and contrastive focus conditions were measured. Results indicated that only the 7-8 year-olds showed the three-way distinction using VOT under (phonemic) contrastive focus, while the other two children groups and adults did not. As for F0, adults made a three-way distinction using F0 in all focus conditions, while the 7-8 and the 10-11 year-olds did so only under limited focus conditions. The 4-5 year-olds did not show the three-way distinction in any focus condition. The results suggest that children build up their phonological awareness and fine-tune phonetic realization in their developmental pathway in conjunction with different functions of information structur

Not all sounds in assimilation environments are perceived equally: Evidence from Korean

Item does not contain fulltextThis study tests whether potential differences in the perceptual robustness of speech sounds influence continuous-speech processes. Two phoneme-monitoring experiments examined place assimilation in Korean. In Experiment 1, Koreans monitored for targets which were either labials (/p,m/) or alveolars (/t,n/), and which were either unassimilated or assimilated to a following /k/ in two-word utterances. Listeners detected unaltered (unassimilated) labials faster and more accurately than assimilated labials; there was no such advantage for unaltered alveolars. In Experiment 2, labial–velar differences were tested using conditions in which /k/ and /p/ were illegally assimilated to a following /t/. Unassimilated sounds were detected faster than illegally assimilated sounds, but this difference tended to be larger for /k/ than for /p/. These place-dependent asymmetries suggest that differences in the perceptual robustness of segments play a role in shaping phonological patterns.11 p