Impact of Renal Replacement Therapy on Rejection among Liver Transplant Recipients.

Introduction: Renal dysfunction in liver transplant recipients is associated with an increased risk of morbidity and mortality, with an even higher risk among patients requiring renal replacement therapy. There is limited data evaluating rejection outcomes in patients requiring renal replacement therapy after liver transplant. Program evaluation aims: To evaluate the incidence of biopsy-proven acute rejection, recipient and graft survival, infection, renal dysfunction, and immunosuppression practices. Design: This was a single-center, retrospective, cohort study. To be eligible, patients were deceased donor liver transplant recipients ≥18 year of age transplanted between January 2017 and August 2019 who received steroid-only induction and tacrolimus as part of their initial immunosuppression regimen. Results: Recipients that required renal replacement therapy (N = 86) were compared to those who received no renal replacement therapy (N = 158). Biopsy-proven acute rejection at 1-year posttransplant was significantly higher among those requiring renal replacement therapy (36% vs 13%, P < .001). Patient survival at 12 months was 77% for those requiring renal replacement therapy and 94% for those not requiring renal replacement therapy (P < .001). Infection (HR 3.8, 95% CI 1.6-8.8; P < .001), but not rejection (HR 0.7, 95% CI 0.3-1.7; P = .5) was an independent predictor of mortality. The use of renal replacement therapy after liver transplant necessitated careful titration of immunosuppression to balance the detrimental risks of infection versus rejection in this high-risk population.

Impact of high MELD scores on CMV viremia following liver transplantation.

INTRODUCTION: Advanced liver disease or cirrhosis is associated with an increased risk of infections; however, the impact of high pretransplant model for end-stage liver disease (MELD) score on cytomegalovirus (CMV) viremia after liver transplantation is unknown. METHODS: This single-center, retrospective, cohort study evaluated CMV high-risk (CMV immunoglobulin G D+/R-) liver transplant recipients who received valganciclovir prophylaxis for 3 months between 2009 and 2019. Patients were stratified by pretransplant MELD score of <35 (low MELD) and ≥35 (high MELD). The primary outcome was 12-month CMV viremia, and secondary outcomes included CMV resistance and tissue invasive disease, mortality, biopsy-proven acute rejection (BPAR), leukopenia, and thrombocytopenia. Multivariable Cox proportional-hazards modeling was used to assess the association of MELD score with the time to CMV viremia. RESULTS: There were 162 and 79 patients in the low and high MELD groups, respectively. Pretransplant MELD score ≥35 was associated with an increased risk of CMV viremia (hazard ratio [HR] 1.73; confidence interval 1.06-2.82, p = .03). CMV viremia occurred at 162 ± 61 days in the low MELD group and 139 ± 62 days in the high MELD group. Although BPAR occurred early at 30 days (13-59) in the low-MELD group and at 18 days (11-66) in the high-MELD group (p = .56), BPAR was not associated with an increased risk of CMV viremia (HR 1.55 [0.93-2.60], p = .1). DISCUSSION: MELD scores ≥35 were associated with an increased hazards of CMV viremia. In liver transplant recipients with MELD scores ≥35 who are CMV high-risk, additional CMV intervention may be warranted.

Impact of Steroid Only Induction on Rejection in Simultaneous Liver-Kidney Transplantation.

Introduction: The occurrence of simultaneous liver kidney transplantation has greatly increased; however, the ideal induction and maintenance immunosuppression remains unknown. Question: This evaluation aimed to determine if corticosteroid only induction in simultaneous liver kidney transplant recipients provided adequate prophylaxis against rejection when compared to basiliximab. Design: This was a single center, retrospective, cohort study of adult simultaneous liver kidney transplant recipients from June 2010 to June 2019 receiving corticosteroid only (N = 41) or basiliximab (N = 42) induction. Results: Liver or kidney biopsy proven acute rejection at 3 months was comparable between the corticosteroid only and basiliximab groups (10% vs 7%, P = .67), which persisted through 12 months posttransplant (15% vs 21%, P = .42). The occurrence of any infection at 3 months was increased in the corticosteroid only group relative to the basiliximab group (41% vs 21%, P = .049). Graft and patient survival at 12 months were similar between groups. Maintenance immunosuppression was overall minimized with a tacrolimus goal of 6-8 ng/mL, mycophenolate mofetil dose reduction to 1000 mg/day by 3 months, and early steroid withdrawal in both groups. Conclusion: Our findings suggested that corticosteroid only induction was an effective strategy for preventing rejection in simultaneous liver kidney transplant recipients, even in combination with reduced maintenance immunosuppression.

Comparison of Alemtuzumab Versus Basiliximab Induction Therapy in Elderly Kidney Transplant Recipients: A Single-Center Experience.

BACKGROUND: The optimal choice of induction immunosuppression for elderly kidney transplant recipients remains unclear. Although alemtuzumab has been associated with escalating risk of death and graft loss in this population, this risk has not been adequately explored. The purpose of this study was to compare the safety and efficacy of alemtuzumab with basiliximab induction in this population. METHODS: This is a retrospective matched cohort study of kidney transplant recipients aged ≥65 years. Patients who received alemtuzumab induction were matched (1:2) to a basiliximab control. The primary outcome was allograft survival. The incidence of acute rejection, infection, and all-cause mortality was measured. RESULTS: Fifty-one and 102 patients were included in the alemtuzumab and basiliximab groups, respectively. Baseline demographics were similar between groups, except for more living donor transplant recipients in the alemtuzumab group (26/51 [51%] vs 31/102 [30.4%], P = .02). Acute cellular rejection occurred more frequently within the first year in the basiliximab group (P = .02). There was no difference in rates of infection within the first year. Graft and patient survival rates were similar over the follow-up period. Patients receiving basiliximab had a higher glomerular filtration rate at 2 years posttransplant (59 mL/min/1.73 m2 vs 49 mL/min/1.73 m2, P = .03). CONCLUSIONS: Alemtuzumab induction is associated with similar outcomes to basiliximab in elderly kidney transplant recipients.

Microbiomes in Canidae.

Because of their range expansion across North America, coyotes (Canis latrans) now occur sympatrically with numerous other predator species, including red foxes (Vulpes vulpes). This raises several interesting ecological questions, including if and how sympatry affects the diet and gut microbiomes of coyotes and red foxes. We examined the gut microbiomes of sympatric populations of coyotes and red foxes within two different National Parks in Virginia, USA, that differ in land use, vegetation, and anthropogenic disturbance: Prince William Forest Park (PRWI) and Manassas National Battlefield Park (MANA). From 2012 to 2017, scat samples from PRWI and MANA were collected and analyzed. Polymerase chain reaction (PCR) amplification of a region of the mitochondrial cytochrome-b gene followed by restriction enzyme digestion of the PCR product was used to determine the origin of each scat sample. Next-Generation DNA sequencing of a hypervariable 16S rRNA gene region was used to determine gut microbiome information about the scat samples. There was no evidence for a difference between the gut microbiomes of red foxes in either location, or for a difference between the gut microbiomes of red foxes at either location and coyotes at the location with lower human disturbance, PRWI. However, the gut microbiomes of coyotes at the location with higher anthropogenic disturbances, MANA, revealed a marked change from those found in red foxes at either location and from those in coyotes at the location with lower disturbances. The gut microbiomes of coyotes subjected to greater human impact may provide evidence of dysbiosis, indicative of increased physiological stress and reduced health. We discuss our observations in the context of understanding anthropogenic impacts on coyote and red fox interactions. Our results suggest that physiological stress in the form of human disturbance may play an important role in the composition of the gut microbiome of coyotes, which can affect their overall health.

Survival benefit of renal transplantation in octogenarians.

BACKGROUND: Elderly patients are the fastest growing population requiring renal replacement therapy. As previous studies have shown a survival benefit of kidney transplantation compared to dialysis for end-stage renal disease, we sought to evaluate if this survival benefit extends to octogenarians. METHODS: This was a single-center retrospective cohort study of renal allograft recipients ≥80 years transplanted from 1999 to 2014 who were compared to patients listed during the same period that did not proceed to transplantation. A secondary matched group was selected from the UNOS transplant waitlist database. The primary outcome was patient survival. Secondary outcomes included graft survival and rejection incidence. RESULTS: Thirty-three transplanted patients were compared to 71 patients waitlisted at our center and 66 patients from the UNOS database. Patients in the study group were transplanted 20.8 ± 16.1 months after listing. Patient survival was 87.8% at 6 months and 1 year and 71.4% at 3 years. Kidney transplantation was associated with a significant decrease in the risk of death after listing (HR: 0.22, CI: 0.11-0.45, P < .001). CONCLUSION: With escalating life expectancy, kidney transplantation is a suitable treatment option in eligible octogenarians.

A Multidisciplinary Technique for Concurrent Panniculectomy-Living Donor Renal Transplantation.

BACKGROUND: Recently, it has been shown that panniculectomy concurrent to living donor renal transplantation is a safe option for management of renal transplant recipients with a large focal pannus. This combined management requires precise coordination of teams. We describe the technique, timing, and sequence for combined renal transplantation and panniculectomy. METHODS: We conducted a retrospective chart review of adult patients (≥18 years old) who underwent simultaneous living donor renal transplantation-panniculectomy from 2015 to 2019. A multi-team approach that included urology, transplant, and plastic surgery was used to perform the combined operations. Typically, the plastic surgery team initiates the operation by performing the panniculectomy. This is followed by kidney transplantation and graft anastomosis. The plastic surgery team then completes the operation with closure of the wound. RESULTS: Twenty patients were identified. Most were male (12:8) with a mean age of 55 years and an average body mass index of 35 kg/m. The mean total operative duration was 394 minutes. On average, 17% of operating time was devoted to panniculectomy. At 90 days follow-up, there was 100% graft survival and all patients had primary graft function. There was a 25% wound complications rate and a 15% reoperation rate. CONCLUSION: By performing panniculectomy first in the sequence, concurrent panniculectomy provides wide exposure and a large operative field for transplantation. Wound closure by plastic surgeons may mitigate the high complication rate commonly seen in obese patients with end-stage renal disease. Future studies are needed to evaluate the cost-benefit of the combined living donor renal transplantation-panniculectomy.

Clinical outcomes of valganciclovir prophylaxis in high-risk (D+/R-) renal transplant recipients experiencing delayed graft function.

BACKGROUND: Cytomegalovirus (CMV) outcomes with valganciclovir prophylaxis in renal transplant recipients experiencing delayed graft function (DGF) are unclear. METHODS: This single center, retrospective, cohort study of CMV high-risk (D+/R- with alemtuzumab induction) deceased donor renal transplant recipients receiving valganciclovir prophylaxis assessed CMV outcomes in patients experiencing DGF (n = 72) versus those with immediate graft function (IGF; n = 66). RESULTS: Cytomegalovirus viremia by 12 months occurred at similar rates in the IGF and DGF groups (30.3% vs 26.4%, respectively, P = 0.71) with 89.7% (35/39) of all cases classified as CMV disease. The median time to CMV viremia post transplant was day 141 and 138 in the IGF and DGF groups, respectively (P = 0.30). The incidence of biopsy-proven acute rejection (BPAR) was higher in the DGF group (18.1% vs 4.6%, P = 0.02) with BPAR preceding CMV in only 1 patient. There was no significant difference in graft loss (1.5% vs 4.2%, P = 0.62) or patient survival (98.5% vs 95.8%, P = 0.62) at 1 year between the IGF and DGF groups, respectively. CONCLUSION: Valganciclovir prophylaxis in patients experiencing DGF yielded similar CMV outcomes up to 1-year post transplant when compared to use in patients with IGF.

Panniculectomy at the time of living donor renal transplantation: An 8-year experience.

Panniculectomy can be performed as a prophylactic procedure preceding transplantation to enable obese patients to meet criteria for renal transplantation. No literature exists on combined renal transplant and panniculectomy surgery (LRT-PAN). We describe our 8-year experience performing LRT-PAN. A retrospective chart review of all patients who had undergone LRT-PAN from 2010 to 2018 was conducted. Data were collected on patient demographics, allograft survival and function, and postoperative course. Fifty-eight patients underwent LRT-PAN. All grafts survived, with acceptable function at 1 year. Median length of stay was 4 days with a mean operative duration of 363 minutes. The wound complication rate was 24%. Ninety-day readmission rate was 52%, with medical causes as the most common reason for readmission (45%), followed by wound (32%) and graft-related complications (23%). Body mass index, diabetes status, and previous immunosuppression did not influence wound complication rate or readmission (P = .7720, P = .0818, and P = .4830, respectively). Combining living donor renal transplant and panniculectomy using a multidisciplinary team may improve access to transplantation, particularly for the obese and postobese population. This combined approach yielded shorter-than-expected hospital stays and similar wound complication rates, and thus should be considered for patients in whom transplantation might otherwise be withheld on the basis of obesity.

Impact of antiretroviral regimen on renal transplant outcomes in HIV-infected recipients.

BACKGROUND: Protease inhibitors (PI) pose a challenge post-transplant due to significant drug interactions with calcineurin inhibitors, prompting many clinicians to convert patients to non-interacting regimens prior to transplant. The purpose of this study was to examine the impact of PI-based regimens on graft outcomes in HIV-infected renal transplant recipients. METHODS: In this retrospective cohort study, 50 HIV-infected renal allograft recipients (27 receiving a PI regimen, 23 receiving a non-PI regimen) transplanted between 2003-2015 were analyzed. RESULTS: Cumulative rejection rates at 12 and 36 months were 41% and 54% in the PI group vs 52% and 86% in the non-PI group. At last follow-up, the overall risk of acute rejection in the PI group was 46% lower compared with the non-PI cohort (P = 0.12). Patients who received a PI-based regimen had significantly reduced graft failure rates (P = 0.027). There was no difference between groups in the degree of interstitial fibrosis/tubular atrophy, arteriolar hyalinosis, arterial sclerosis, or glomerular sclerosis on available biopsies, despite longer follow-up time in the PI group. CONCLUSIONS: Our study suggests that PI-based antiretroviral therapy regimens are associated with improved graft survival and that patients can achieve adequate outcomes on a PI-based regimen when necessary. Due to study limitations, further studies are needed to determine the optimal immunosuppression/antiretroviral therapy regimen post-transplant.

Collaborative practice agreement in solid organ transplantation.

Background Given the complexity of solid organ transplant recipients, a multidisciplinary approach is required. To promote medication safety and enable providers to focus on the medical and surgical needs of these patients, our department of pharmacy created a collaborative practice agreement between physicians and pharmacists. Through this agreement, credentialed pharmacists are empowered to provide inpatient services including initiation and adjustment of medications through independent review of laboratory results after multidisciplinary rounds. Objective To evaluate the effect of our collaborative practice agreement on clinical care and institutional finances. Setting An inpatient setting at a large academic medical center. Methods Three transplant pharmacists entered all clinical interventions made on abdominal transplant recipients between September and October 2013 into Quantifi®, a software application that categorizes and assigns a cost savings value based on impact and type of intervention. Main outcome measure The main outcome measures in this study were number and categorization of interventions, as well as estimated cost savings to the institution. Results There were 1060 interventions recorded, an average of 20 interventions per pharmacist per day. The most common interventions were pharmacokinetic evaluations (36%) and dose adjustments (19%). Over the time period, these interventions translated into an estimated savings of $107,634.00, or an annual cost savings of $373,131.20 per pharmacist, or a cost-benefit ratio of 2.65 to the institution. Conclusions Based on our study, implementation of a collaborative practice agreement enables credentialed pharmacists to make clinically and financially meaningful interventions in a complex patient population.

Increased extra-pair paternity in broods of aging males and enhanced recruitment of extra-pair young in a migratory bird.

Despite keen interest in extra-pair mating in birds, its adaptive significance remains unresolved. Here, we use a multi-year dataset to test whether traits of a female's social mate influence her propensity to produce extra-pair offspring in a population of house wrens, and whether producing extra-pair young has consequences for a female's fitness through effects on offspring survival. Females were most likely to produce extra-pair offspring when paired with old males and when paired with males on poor-quality territories, although this latter effect was marginally nonsignificant. Among offspring, the cutaneous immunity of within-pair young decreased as the age of their sires increased, but cutaneous immunity of extra-pair young was not affected by the age of their extra-pair sires or by the age of the males rearing them. Extra-pair offspring were more likely than within-pair offspring to return as breeding adults to the local population, with extra-pair sons being more likely to return as a breeder for multiple years. Our findings support the hypothesis that females produce extra-pair offspring to enhance their inclusive fitness beyond what they are capable of given the male with which they are socially paired.

Genetic and environmental variation in condition, cutaneous immunity, and haematocrit in house wrens.

BACKGROUND: Life-history studies of wild bird populations often focus on the relationship between an individual's condition and its capacity to mount an immune response, as measured by a commonly-employed assay of cutaneous immunity, the PHA skin test. In addition, haematocrit, the packed cell volume in relation to total blood volume, is often measured as an indicator of physiological performance. A multi-year study of a wild population of house wrens has recently revealed that those exhibiting the highest condition and strongest PHA responses as nestlings are most likely to be recruited to the breeding population and to breed through two years of age; in contrast, intermediate haematocrit values result in the highest recruitment to the population. Selection theory would predict, therefore, that most of the underlying genetic variation in these traits should be exhausted resulting in low heritability, although such traits may also exhibit low heritability because of increased residual variance. Here, we examine the genetic and environmental variation in condition, cutaneous immunity, and haematocrit using an animal model based on a pedigree of approximately 2,800 house wrens. RESULTS: Environmental effects played a paramount role in shaping the expression of the fitness-related traits measured in this wild population, but two of them, condition and haematocrit, retained significant heritable variation. Condition was also positively correlated with both the PHA response and haematocrit, but in the absence of any significant genetic correlations, it appears that this covariance arises through parallel effects of the environment acting on this suite of traits. CONCLUSIONS: The maintenance of genetic variation in different measures of condition appears to be a pervasive feature of wild bird populations, in contradiction of conventional selection theory. A major challenge in future studies will be to explain how such variation persists in the face of the directional selection acting on condition in house wrens and other species.

Neonatal body condition, immune responsiveness, and hematocrit predict longevity in a wild bird population.

Measures of body condition, immune function, and hematological health are widely used in ecological studies of vertebrate populations, predicated on the assumption that these traits are linked to fitness. However, compelling evidence that these traits actually predict long-term survival and reproductive success among individuals in the wild is lacking. Here, we show that body condition (i.e., size-adjusted body mass) and cutaneous immune responsiveness to phytohaemagglutinin (PHA) injection among neonates positively predict recruitment and subsequent longevity in a wild, migratory population of house wrens (Troglodytes aedon). However, neonates with intermediate hematocrit had the highest recruitment and longevity. Neonates with the highest PHA responsiveness and intermediate hematocrit prior to independence eventually produced the most offspring during their lifetime breeding on the study site. Importantly, the effects of PHA responsiveness and hematocrit were revealed while controlling for variation in body condition, sex, and environmental variation. Thus, our data demonstrate that body condition, cutaneous immune responsiveness, and hematocrit as a neonate are associated with individual fitness. Although hematocrit's effect is more complex than traditionally thought, our results suggest a previously underappreciated role for this trait in influencing survival in the wild.

Evidence for heterozygote instability in microsatellite loci in house wrens.

Microsatellite loci have high mutation rates and high levels of allelic variation, but the factors influencing their mutation rate are not well understood. The proposal that heterozygosity may increase mutation rates has profound implications for understanding the evolution of microsatellite loci, but currently has limited empirical support. We examined 20 microsatellite mutations identified in an analysis of 12 260 meiotic events across three loci in two populations of a songbird, the house wren (Troglodytes aedon). We found that for an allele of a given length, mutation was significantly more likely when there was a relatively large difference in size between the allele and its homologue (i.e. a large 'allele span'). Our results support the proposal of heterozygote instability at microsatellite loci.

Extra-pair young in house wren broods are more likely to be male than female.

Sex-allocation theory predicts that females should preferentially produce offspring of the sex with greater fitness potential. In socially monogamous animal species, extra-pair mating often increases the variance in fitness of sons relative to daughters. Thus, in situations where offspring sired by a female's extra-pair mate(s) will typically have greater fitness potential than offspring sired by the within-pair mate, sex-allocation theory predicts that females will bias the sex of offspring sired by extra-pair mates towards male. We examined the relationship between offspring sex and paternity over six breeding seasons in an Illinois population of the house wren (Troglodytes aedon), a cavity-nesting songbird. Out of the 2345 nestlings that had both sex and paternity assigned, 350 (15%) were sired by extra-pair males. The sex ratio of extra-pair offspring, 0.534, was significantly greater than the sex ratio of within-pair offspring, 0.492, representing an increase of 8.5 per cent in the proportion of sons produced. To our knowledge, this is the first confirmed report of female birds increasing their production of sons in association with extra-pair fertilization. Our results are consistent with the oft-mentioned hypothesis that females engage in extra-pair mating to increase offspring quality.

Female house wrens (Troglodytes aedon) increase the size, but not immunocompetence, of their offspring through extra-pair mating.

House wrens are typically socially monogamous, but frequently engage in extra-pair matings leading to multisired broods. Because females do not appear to acquire direct material benefits from their extra-pair mates, we tested the hypothesis that female house wrens derive indirect genetic benefits, such as enhanced immunocompetence (cutaneous immune activity, humoral immunity, and plasma bactericidal activity) and condition (size and haematoserological traits) for their offspring, by mating polyandrously. We predicted that extra-pair young (EPY) should show greater immune responsiveness and better body condition than their within-pair maternal half-siblings (WPY). Contrary to our prediction, WPY had higher cutaneous immune activity than their EPY brood-mates in two of three years, and EPY and WPY did not differ in measures of innate and humoral immunity. WPY also had higher albumin to gamma-globulin ratios than EPY; however, they were not in better condition based on other measures. EPY had consistently longer tarsi (a measure of long-bone size) than their WPY half-siblings, suggesting that females engage in extra-pair copulations with larger males. The benefits of large structural size in the study population is unknown, but based on evidence from other passerines, we suggest that structural size may be an important fitness-related trait in house wrens. We conclude that our results are not consistent with the hypothesis that females gain immune-related benefits for their offspring by engaging in extra-pair matings. Further study of the fitness consequences of differences in tarsus length is needed to determine whether females acquire size-related benefits for their offspring from extra-pair mates.

Genotype and extra-pair paternity in the house wren: a rare-male effect?

Females in socially monogamous species may select extra-pair (EP) mates to increase the heterozygosity, and hence fitness, of their offspring. We tested this hypothesis in the house wren (Troglodytes aedon), a largely monogamous songbird in which EP young are common. We typed paired males and females, nestlings, and males on neighbouring territories, at five to seven microsatellite loci over 2 years in a Wyoming, USA, population. We identified EP sires at 20 nests with EP young. In pairwise comparisons, we found no significant differences between cuckolded within-pair (WP) males and EP sires in three measures of heterozygosity (mean d2, standardized heterozygosity and internal relatedness). However, EP sires had fewer alleles that were common within the population than did the WP males they cuckolded. Nearby males who were EP sires also had fewer common alleles than did nearby males who did not sire EP young. Females in our population may be more prone to accept copulations from males with rare genotypes than from males with common genotypes. Alternatively, selection of rare-male sperm may occur within the female reproductive tract. Because mating with rare males is likely to increase offspring heterozygosity, our data suggest that EP mating may provide genetic benefits to females.

Expression of PTPRO during mouse development suggests involvement in axonogenesis and differentiation of NT-3 and NGF-dependent neurons.

Competition and cooperation between type II and type III receptor protein tyrosine phosphatases (RPTPs) regulate axon extension and pathfinding in Drosophila. The first step to investigate whether RPTPs influence axon growth in the more complex vertebrate nervous system is to identify which neurons express a particular RPTP. We studied the expression of mouse PTPRO, a type III RPTP with an extracellular region containing eight fibronectin type III domains, during embryogenesis and after birth. Mouse PTPRO mRNA is expressed exclusively in two cell types: neurons and kidney podocytes. Maximal expression in the brain was coincident with mid to late gestation and axonogenesis in the brain. We cloned two cDNAs, including a splice variant without sequence coding of 28 amino acids within the juxtamembrane domain that was found mostly in kidney. In situ hybridization detected mPTPRO mRNA in the cerebral cortex, olfactory bulb and nucleus, hippocampus, motor neurons, and the spinal cord midline. In addition, mPTPRO mRNA was found throughout dorsal root, cranial, and sympathetic ganglia and within kidney glomeruli. Mouse PTPRO mRNA was observed in neuron populations expressing TrkA, the high-affinity nerve growth factor receptor, or TrkC, the neurotrophin-3 receptor, and immunoreactive mPTPRO and TrkC colocalized in large dorsal root ganglia proprioceptive neurons. Our results suggest that mPTPRO is involved in the differentiation and axonogenesis of central and peripheral nervous system neurons, where it is in a position to modulate intracellular responses to neurotrophin-3 and/or nerve growth factor.

SHP-2 mediates target-regulated axonal termination and NGF-dependent neurite growth in sympathetic neurons.

The tyrosine phosphatase SHP-2 has been implicated in a variety of signaling pathways, including those mediated by neurotrophins in neurons. To examine the role of SHP-2 in the development of sympathetic neurons, we inhibited the function of SHP-2 in transgenic mice by overexpressing a catalytically inactive SHP-2 mutant under the control of the human dopamine beta-hydroxylase promoter. Expression of mutant SHP-2 did not influence the survival, axon initiation, or pathfinding abilities of the sympathetic neurons. However, mutant SHP-2 expression resulted in an overproduction of sympathetic fibers in sympathetic target organs. This was due to interference with SHP-2 function, as overexpression of wild type SHP-2 had no such effect. In vitro, NGF-dependent neurite growth was inhibited in neurons expressing mutant SHP-2 but not in those expressing wild type SHP-2. Mutant (but not wt) SHP-2 expression also inhibited NGF-stimulated ERK activation. The NGF-dependent survival pathway was less affected than the neurite growth pathway. Our results suggest that NGF-regulated axon growth signals, and to a lesser degree survival signals, are mediated through a SHP-2-dependent pathway in sympathetic neurons. The increased sympathetic innervation in target tissues of neurons expressing mutant SHP-2 may result from interference with normal "stop" signals dependent on signaling by gradients of NGF.