UNC-116 and UNC-16 function with the NEKL-3 kinase to promote axon targeting.

KIF5C is a kinesin-1 heavy chain that has been associated with neurodevelopmental disorders. Although the roles of kinesin-1 in axon transport are well known, little is known about how it regulates axon targeting. We report that UNC-116/KIF5C functions with the NEKL-3/NEK6/7 kinase to promote axon targeting in Caenorhabditis elegans. Loss of UNC-116 causes the axon to overshoot its target and UNC-116 gain-of-function causes premature axon termination. We find that loss of the UNC-16/JIP3 kinesin-1 cargo adaptor disrupts axon termination, but loss of kinesin-1 light chain function does not affect axon termination. Genetic analysis indicates that UNC-16 functions with the NEKL-3 kinase to promote axon termination. Consistent with this observation, imaging experiments indicate that loss of UNC-16 and UNC-116 disrupt localization of NEKL-3 in the axon. Moreover, genetic interactions suggest that NEKL-3 promotes axon termination by functioning with RPM-1, a ubiquitin ligase that regulates microtubule stability in the growth cone. These observations support a model where UNC-116 functions with UNC-16 to promote localization of NEKL-3 in the axon. NEKL-3, in turn, functions with the RPM-1 ubiquitin ligase to promote axon termination.

The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1.

A family of giant KASH proteins, including C. elegans ANC-1 and mammalian Nesprin-1 and -2, are involved in organelle anchoring and are associated with multiple neurodevelopmental disorders including autism, bipolar disorder, and schizophrenia. However, little is known about how these proteins function in neurons. Moreover, the role of organelle anchoring in axon development is poorly understood. Here, we report that ANC-1 functions with the SLT-1 extracellular guidance cue to polarize ALM axon growth. This role for ANC-1 is specific to its longer ANC-1A and ANC-1C isoforms, suggesting that it is mechanistically distinct from previously described roles for ANC-1. We find that ANC-1 is required for the localization of a cluster of mitochondria to the base of the proximal axon. Furthermore, genetic and pharmacological studies indicate that ANC-1 functions with mitochondria to promote polarization of ALM axon growth. These observations reveal a mechanism whereby ANC-1 functions through mitochondria to polarize axon growth in response to SLT-1.

Importance of social vulnerability on long-term outcomes after heart transplantation.

The relationship between social determinants of health and outcomes after heart transplantation has not been examined. The social vulnerability index (SVI) uses United States census data to determine the social vulnerability of every census tract based on 15 factors. This retrospective study seeks to examine the impact of SVI on outcomes after heart transplantation. Adult heart recipients who received a graft between 2012 and 2021 were stratified into SVI percentiles of <75% and SVI of ≥75%. The primary endpoint was survival. The median SVI was 48% (interquartile range: 30%-67%) among 23 700 recipients. One-year survival was similar between groups (91.4 vs 90.7%, log-rank P = .169); however, 5-year survival was lower among individuals living in vulnerable communities (74.8% vs 80.0%, P < .001). This finding persisted despite risk adjustment for other factors associated with mortality (survival time ratio 0.819, 95% confidence interval: 0.755-0.890, P < .001). The incidences of 5-year hospital readmission (81.4% vs 75.4%, P < .001) and graft rejection (40.3% vs 35.7%, P = .004) were higher among individuals living in vulnerable communities. Individuals living in vulnerable communities may be at increased risk of mortality after heart transplantation. These findings suggest there is an opportunity to focus on these recipients undergoing heart transplantation to improve survival.

Sounding the Alarm: What Clinicians Need to Know about Physical, Emotional, and Cognitive Recovery After Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVE: We summarize the existing data on the occurrence of physical, emotional, and cognitive dysfunction associated with postintensive care syndrome (PICS) in adult survivors of venoarterial extracorporeal membrane oxygenation (VA-ECMO). DATA SOURCES: MEDLINE, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched. STUDY SELECTION: Peer-reviewed studies of adults receiving VA-ECMO for any reason with at least one measure of health-related quality of life outcomes or PICS at long-term follow-up of at least 6 months were included. DATA EXTRACTION: The participant demographics and baseline characteristics, in-hospital outcomes, long-term health outcomes, quality of life outcome measures, and prevalence of PICS were extracted. DATA SYNTHESIS: Twenty-seven studies met inclusion criteria encompassing 3,271 patients who were treated with VA-ECMO. The studies were limited to single- or two-center studies. Outcomes variables and follow-up time points evaluated were widely heterogeneous which limits comprehensive analysis of PICS after VA-ECMO. In general, the longer-term PICS-related outcomes of survivors of VA-ECMO were worse than the general population, and approaching that of patients with chronic disease. Available studies identified high rates of abnormal 6-minute walk distance, depression, anxiety, and posttraumatic stress disorder that persisted for years. Half or fewer survivors return to work years after discharge. Only 2 of 27 studies examined cognitive outcomes and no studies evaluated cognitive dysfunction within the first year of recovery. No studies evaluated the impact of targeted interventions on these outcomes. CONCLUSIONS: Survivors of VA-ECMO represent a population of critically ill patients at high risk for deficits in physical, emotional, and cognitive function related to PICS. This systematic review highlights the alarming reality that PICS and in particular, neurocognitive outcomes, in survivors of VA-ECMO are understudied, underrecognized, and thus likely undertreated. These results underscore the imperative that we look beyond survival to focus on understanding the burden of survivorship with the goal of optimizing recovery and outcomes after these life-saving interventions. Future prospective, multicenter, longitudinal studies in recovery after VA-ECMO are justified.

De-implementation of Axillary Dissection in Women Undergoing Mastectomy for Breast Cancer.

BACKGROUND: Completion axillary lymph node dissection (cALND) was standard treatment for breast cancer with positive sentinel lymph nodes (SLNs) until 2011, when data from the Z11 and AMAROS trials challenged its survival benefit in early stage breast cancer. We assessed the contribution of patient, tumor, and facility factors on cALND use in patients undergoing mastectomy and SLN biopsy. PATIENTS AND METHODS: Using the National Cancer Database, patients diagnosed from 2012 to 2017 who underwent upfront mastectomy and SLN biopsy with at least one positive SLN were included. A multivariable mixed effects logistic regression model was used to determine the effect of patient, tumor, and facility variables on cALND use. Reference effect measures (REM) were used to compare the contribution of general contextual effects (GCE) to variation in cALND use. RESULTS: From 2012 to 2017, the overall use of cALND decreased from 81.3% to 68.0%. Overall, younger patients, larger tumors, higher grade tumors, and tumors with lymphovascular invasion were more likely to undergo cALND. Facility variables, including higher surgical volume and facility location in the Midwest, were associated with increased use of cALND. However, REM results showed that the contribution of GCE to the variation in cALND use exceeded that of the measured patient, tumor, facility, and time variables. CONCLUSIONS: There was a decrease in cALND use during the study period. However, cALND was frequently performed in women after mastectomy found to have a positive SLN. There is high variability in cALND use, mainly driven by interfacility practice variation rather than specific high-risk patient and/or tumor characteristics.

Unmeasured factors are associated with the use of completion lymph node dissection (CLND) in melanoma.

BACKGROUND: Completion lymph node dissection (CLND) was the standard treatment for patients with melanoma with positive sentinel lymph nodes (SLN) until 2017 when data from the DeCOG-SLT and MLST-2 randomized trials challenged the survival benefit of this procedure. We assessed the contribution of patient, tumor and facility factors on the use of CLND in patients with surgically resected Stage III melanoma. METHODS: Using the National Cancer Database, patients who underwent surgical excision and were found to have a positive SLN from 2012 to 2017 were included. A multivariable mixed-effects logistic regression model with a random intercept for the facility was used to determine the effect of patient, tumor, and facility variables on the risk of CLND. Reference effect measures (REMs) were used to compare the contribution of contextual effects (unknown facility variables) versus measured variables on the variation in CLND use. RESULTS: From 2012 to 2017, the overall use of CLND decreased from 59.9% to 26.5% (p < 0.0001). Overall, older patients and patients with government-based insurance were less likely to undergo CLND. Tumor factors associated with a decreased rate of CLND included primary tumor location on the lower limb, decreasing depth, and mitotic rate <1. However, the contribution of contextual effects to the variation in CLND use exceeded that of the measured facility, tumor, time, and patient variables. CONCLUSIONS: There was a decrease in CLND use during the study period. However, there is still high variability in CLND use, mainly driven by unmeasured contextual effects.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.

Common and rare variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

A National Survey of Motor Vehicle Crashes Among General Surgery Residents.

OBJECTIVES: Evaluate the frequency of self-reported, post-call hazardous driving events in a national cohort of general surgery residents and determine the associations between duty hour policy violations, psychiatric well-being, and hazardous driving events. SUMMARY OF BACKGROUND DATA: MVCs are a leading cause of resident mortality. Extended work shifts and poor psychiatric well-being are risk factors for MVCs, placing general surgery residents at risk. METHODS: General surgery residents from US programs were surveyed after the 2017 American Board of Surgery In-Training Examination. Outcomes included self-reported nodding off while driving, near-miss MVCs, and MVCs. Group-adjusted cluster Chi-square and hierarchical regression models with program-level intercepts measured associations between resident- and program-level factors and outcomes. RESULTS: Among 7391 general surgery residents from 260 programs (response rate 99.3%), 34.7% reported nodding off while driving, 26.6% a near-miss MVC, and 5.0% an MVC over the preceding 6 months. More frequent 80-hour rule violations were associated with all hazardous driving events: nodding off while driving {59.8% with ≥5 months with violations vs 27.2% with 0, adjusted odds ratio (AOR) 2.86 [95% confidence interval (CI) 2.21-3.69]}, near-miss MVCs, [53.6% vs 19.2%, AOR 3.28 (95% CI 2.53-4.24)], and MVCs [14.0% vs 3.5%, AOR 2.46 (95% CI 1.65-3.67)]. Similarly, poor psychiatric well-being was associated with all 3 outcomes [eg, 8.0% with poor psychiatric well-being reported MVCs vs 2.6% without, odds ratio 2.55 (95% CI 2.00-3.24)]. CONCLUSIONS: Hazardous driving events are prevalent among general surgery residents and associated with frequent duty hour violations and poor psychiatric well-being. Greater adherence to duty hour standards and efforts to improve well-being may improve driving safety.

Multi-institution Evaluation of Adherence to Comprehensive Postoperative VTE Chemoprophylaxis.

OBJECTIVES: The aims of this study were to: (1) measure the rate of failure to provide defect-free postoperative venous thromboembolism (VTE) chemoprophylaxis, (2) identify reasons for failure to provide defect-free VTE chemoprophylaxis, and (3) examine patient- and hospital-level factors associated with failure. SUMMARY BACKGROUND DATA: Current VTE quality measures are inadequate. VTE outcome measures are invalidated for interhospital comparison by surveillance bias. VTE process measures (e.g., SCIP-VTE-2) do not comprehensively capture failures throughout patients' entire hospitalization. METHODS: We examined adherence to a novel VTE chemoprophylaxis process measure in patients who underwent colectomies over 18 months at 36 hospitals in a statewide surgical collaborative. This measure assessed comprehensive VTE chemoprophylaxis during each patient's entire hospitalization, including reasons why chemoprophylaxis was not given. Associations of patient and hospital characteristics with measure failure were examined. RESULTS: The SCIP-VTE-2 hospital-level quality measure identified failures of VTE chemoprophylaxis in 0% to 3% of patients. Conversely, the novel measure unmasked failure to provide defect-free chemoprophylaxis in 18% (736/4086) of colectomies. Reasons for failure included medication not ordered (30.4%), patient refusal (30.3%), incorrect dosage/frequency (8.2%), and patient off-unit (3.4%). Patients were less likely to fail the chemoprophylaxis process measure if treated at nonsafety net hospitals (OR 0.62, 95% CI 0.39-0.99, P = 0.045) or Magnet designated hospitals (OR 0.45, 95% CI 0.29-0.71, P = 0.001). CONCLUSIONS: In contrast to SCIP-VTE-2, our novel quality measure unmasked VTE chemoprophylaxis failures in 18% of colectomies. Most failures were due to patient refusals or ordering errors. Hospitals should focus improvement efforts on ensuring patients receive VTE prophylaxis throughout their entire hospitalization.

Leveraging a Comprehensive Program to Implement a Colorectal Surgical Site Infection Reduction Bundle in a Statewide Quality Improvement Collaborative.

OBJECTIVES: Our objective was to examine the implementation and associated clinical outcomes of a comprehensive surgical site infection (SSI) reduction bundle in a large statewide surgical quality improvement collaborative leveraging a multifaceted implementation strategy. SUMMARY BACKGROUND DATA: Bundled perioperative interventions reduce colorectal SSI rates when enacted at individual hospitals, but the ability to implement comprehensive SSI bundles and to examine the resultant clinical effectiveness within a larger, diverse population of hospitals is unknown. METHODS: A multifaceted SSI reduction bundle was developed and implemented in a large statewide surgical quality improvement collaborative through a novel implementation program consisting of guided implementation, data feedback, mentorship, process improvement training/coaching, and targeted-implementation toolkits. Bundle adherence and ACS NSQIP outcomes were examined preimplementation versus postimplementation. RESULTS: Among 32 hospitals, there was a 2.5-fold relative increase in the proportion of patients completing at least 75% of bundle elements (preimplementation = 19.5% vs. postimplementation = 49.8%, P = 0.001). Largest adherence gains were seen in wound closure re-gowning/re-gloving (24.0% vs. 62.0%, P < 0.001), use of clean closing instruments (32.1% vs. 66.2%, P = 0.003), and preoperative chlorhexidine bathing (46.1% vs. 77.6%, P < 0.001). Multivariable analyses showed a trend toward lower risk of superficial incisional SSI in the postimplementation period compared to baseline (OR 0.70, 95% CI 0.49-10.2, P = 0.06). As the adherence in the number of bundle elements increased, there was a significant decrease in superficial SSI rates (lowest adherence quintile, 4.6% vs. highest, 1.5%, P < 0.001). CONCLUSIONS: A comprehensive multifaceted SSI reduction bundle can be successfully implemented throughout a large quality improvement learning collaborative when coordinated quality improvement activities are leveraged, resulting in a 30% decline in SSI rates. Lower superficial SSI rates are associated with the number of adherent bundle elements a patient receives, rendering considerable benefits to institutions capable of implementing more components of the bundle.

Gender Differences in Utilization of Duty-hour Regulations, Aspects of Burnout, and Psychological Well-being Among General Surgery Residents in the United States.

OBJECTIVE: The aim of the study was to (1) assess differences in how male and female general surgery residents utilize duty-hour regulations and experience aspects of burnout and psychological well-being, and (2) to explore reasons why these differing experiences exist. BACKGROUND: There may be differences in how women and men enter, experience, and leave residency programs. METHODS: A total of 7395 residents completed a survey (response rate = 99%). Logistic regression models were developed to examine the association between gender and resident outcomes. Semistructured interviews were conducted with 42 faculty and 56 residents. Transcripts were analyzed thematically using a constant comparative approach. RESULTS: Female residents reported more frequently staying in the hospital >28 hours or working >80 hours in a week (≥3 times in a month, P < 0.001) and more frequently feeling fatigued and burned out from their work (P < 0.001), but less frequently "treating patients as impersonal objects" or "not caring what happens" to them (P < 0.001). Women reported more often having experienced many aspects of poor psychological well-being such as feeling unhappy and depressed or thinking of themselves as worthless (P < 0.01). In adjusted analyses, associations remained significant. Themes identified in the qualitative analysis as possible contributory factors to gender differences include a lack of female mentorship/leadership, dual-role responsibilities, gender blindness, and differing pressures and approaches to patient care. CONCLUSIONS: Female residents report working more, experiencing certain aspects of burnout more frequently, and having poorer psychological well-being. Qualitative themes provide insights into possible cultural and programmatic shifts to address the concerns for female residents.

SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase.

During development, axons must integrate directional information encoded by multiple guidance cues and their receptors. Axon guidance receptors, such as UNC-40 (DCC) and SAX-3 (Robo), can function individually or combinatorially with other guidance receptors to regulate downstream effectors. However, little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. Here, we show that UNC-40, SAX-3 and the SYD-1 RhoGAP-like protein function interdependently to regulate the MIG-2 (Rac) GTPase in the HSN axon of C. elegans. We find that SYD-1 mediates an UNC-6 (netrin) independent UNC-40 activity to promote ventral axon guidance. Genetic analysis suggests that SYD-1 function in axon guidance requires both UNC-40 and SAX-3 activity. Moreover, the cytoplasmic domains of UNC-40 and SAX-3 bind to SYD-1 and SYD-1 binds to and negatively regulates the MIG-2 (Rac) GTPase. We also find that the function of SYD-1 in axon guidance is mediated by its phylogenetically conserved C isoform, indicating that the role of SYD-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. Our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector, providing a potential means for the integration of guidance signals.

Food and Drug Administration, American Academy of Ophthalmology, American Academy of Optometry, American Association for Pediatric Ophthalmology and Strabismus, American Optometric Association, American Society of Cataract and Refractive Surgery, and Contact Lens Association of Ophthalmologists Co-Sponsored Workshop: Controlling the Progression of Myopia: Contact Lenses and Future Medical Devices.

The prevalence of myopia is high and increasing. Approximately 5 billion people around the world are expected to be myopic by the year 2050. Methods to slow the progression of myopia and therefore potentially decrease the associated sight-threatening complications have been the subject of a number of investigations. A workshop, sponsored by the United States Food and Drug Administration (FDA) Center for Devices and Radiological Health, American Academy of Ophthalmology, American Academy of Optometry, American Association for Pediatric Ophthalmology and Strabismus, American Optometric Association, American Society of Cataract and Refractive Surgery, and Contact Lens Association of Ophthalmologists, Inc, convened myopia experts from around the world to discuss principles to consider in the design of clinical trials investigating the effectiveness and safety of myopia control devices. Experts discussed parameters such as study endpoints, duration, enrollment criteria, patient-reported outcomes, recruitment, and retention. The discussions among the experts, FDA, and audience members should help to facilitate the development and evaluation of reasonably safe and effective myopia control devices.

Transition between synaptic branch formation and synaptogenesis is regulated by the lin-4 microRNA.

Axonal branch formation and synaptogenesis are sequential events that are required for the establishment of neuronal connectivity. However, little is known about how the transition between these two events is regulated. Here, we report that the lin-4 microRNA can regulate the transition between branch formation and synaptogenesis in the PLM axon of C. elegans. The PLM axon grows a collateral branch during the early L1 stage and undergoes synaptogenesis during the late L1 stage. Loss of the lin-4 microRNA disrupts synaptogenesis during the late L1 stage, suggesting that lin-4 promotes synaptogenesis. Conversely, the target of lin-4, the LIN-14 transcription factor, promotes PLM branch formation and inhibits synaptogenesis during the early L1 stage. Moreover, we present genetic evidence suggesting that synaptic vesicle transport is required for PLM branch formation and that the role of LIN-14 is to promote transport of synaptic vesicles to the region of future branch growth. These observations provide a novel mechanism whereby lin-4 promotes the transition from branch formation to synaptogenesis by repressing the branch-promoting and synaptogenesis-inhibiting activities of LIN-14.

MIG-10 functions with ABI-1 to mediate the UNC-6 and SLT-1 axon guidance signaling pathways.

Extracellular guidance cues steer axons towards their targets by eliciting morphological changes in the growth cone. A key part of this process is the asymmetric recruitment of the cytoplasmic scaffolding protein MIG-10 (lamellipodin). MIG-10 is thought to asymmetrically promote outgrowth by inducing actin polymerization. However, the mechanism that links MIG-10 to actin polymerization is not known. We have identified the actin regulatory protein ABI-1 as a partner for MIG-10 that can mediate its outgrowth-promoting activity. The SH3 domain of ABI-1 binds to MIG-10, and loss of function of either of these proteins causes similar axon guidance defects. Like MIG-10, ABI-1 functions in both the attractive UNC-6 (netrin) pathway and the repulsive SLT-1 (slit) pathway. Dosage sensitive genetic interactions indicate that MIG-10 functions with ABI-1 and WVE-1 to mediate axon guidance. Epistasis analysis reveals that ABI-1 and WVE-1 function downstream of MIG-10 to mediate its outgrowth-promoting activity. Moreover, experiments with cultured mammalian cells suggest that the interaction between MIG-10 and ABI-1 mediates a conserved mechanism that promotes formation of lamellipodia. Together, these observations suggest that MIG-10 interacts with ABI-1 and WVE-1 to mediate the UNC-6 and SLT-1 guidance pathways.

UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In Caenorhabditis elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1 (LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, 2 genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.

UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.

MAPK8IP3 (unc-16/JIP3) is a neurodevelopmental-disorder associated gene that can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.