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PubMed1999

Clinical features and treatment interventions for human immunodeficiency virus-associated neurologic disease in children.

HIV-1 infection in children and adolescents can cause progressive neurologic disease, affective brain growth, motor function, and neurodevelopment. In addition, myelopathies, neuropathies, myopathies, strokes, and psychiatric or behavioral manifestations can be a result of HIV-1 infection, OI, or toxicities of treatment interventions. CNS OI are important causes of morbidity and mortality, often mimicking the HIV-1 associated neurologic syndromes. Psychometric, clinical, neuroradiologic, and laboratory testing are valuable for diagnostic and treatment decisions. The cornerstone of treating HIV-1-associated neurologic disease is providing an effective regimen of antiretroviral drugs to reduce the viral burden. It is also necessary to provide rehabilitation, optimize nutrition, supply appropriate antimicrobial prophylaxis against OI, minimize pain, and treat neurobehavioral or psychiatric complications. Efforts at preventing HIV-1 infection are important for diminishing and allaying the growth of this international pandemic.

Central Nervous System Diseases↗

PubMed2001

Correlation between prenatal velocity waveforms in the aortic isthmus and neurodevelopmental outcome between the ages of 2 and 4 years.

OBJECTIVE: Experimental studies on fetal lambs have shown that during an increase in the resistance to placental flow the delivery of oxygen to the brain is preserved as long as net flow through the aortic isthmus is antegrade. Our purpose was to determine whether the same changes in aortic isthmus flow in human subjects have any impact on neurodevelopmental outcome. STUDY DESIGN: Forty-four fetuses were retrospectively included in this study on the basis of an abnormal Doppler velocity in the umbilical artery. Mean gestational age at delivery was 33.0 +/- 2.0 weeks and mean birth weight 1386 +/- 435 g. The neurodevelopmental condition was assessed between the ages of 2 and 4 years. The developmental score was analyzed in relation to the flow patterns in the fetal aortic isthmus, which were classified as follows: group A, net isthmic flow antegrade (defined as the ratio of the systolic antegrade to the diastolic retrograde velocity integrals) (n = 39); group B, net isthmic flow retrograde (n = 5). RESULTS: Nonoptimal neurodevelopment was observed in 19 (49%) of 39 fetuses in group A and in all 5 fetuses (100%) in group B. This difference is significant and leads to a relative risk of 2.05 (95% confidence interval, 1.49-2.83) for neurodevelopmental deficit when predominantly retrograde flow is observed in the fetal aortic isthmus before birth. CONCLUSION: Measuring the ratio of antegrade to retrograde velocity integrals in the aortic isthmus could help in the indirect assessment of cerebral oxygenation during placental circulatory insufficiency.

Aorta↗

PubMed2002

Perinatal predictors of neurodevelopmental outcome in small-for-gestational-age children at 18 months of age.

OBJECTIVE: Our purpose was to explore the influence of a range of perinatal variables on neurodevelopment at 18 months in a cohort of small-for-gestational-age (SGA) children born in the mid 1990s. STUDY DESIGN: Two hundred eighty-two SGA children (birth weight <10th centile) were followed up prospectively; 220 (78%) had Bayley Scales of Infant Development II performed at 18 months' corrected age. RESULTS: The mean (SD) gestation at delivery was 36.5 (2.7) weeks and mean birth weight was 2095 (549) g. The mean Bayley Scales of Infant Development scores were as follows: Mental Developmental Index score, 95.6 (14.5); Psychomotor Developmental Index score, 97.9 (14.8); and Behavioural Rating Scale score, 110.6 (13.5). SGA children whose mothers had pregnancy-induced hypertension were less likely to have low Mental Development Index scores than SGA children whose mothers were normotensive during pregnancy (10 [23%] vs 78 [44%]. P =.01). Low Psychomotor Development Index scores were associated with not being breast-fed at 3 months (odds ratio [OR] 3.5; 95% CI 1.2-10.1) and long neonatal nursery stay (OR 2.8, 95% CI 1.02-7.05). A low Behavioral Rating Scale score was associated with a large z score for head circumference at birth (OR 2.4, 95% CI 1.2-4.8) and cord arterial base deficit (OR 1.2, 95% CI 1.01-1.4). CONCLUSION: Few of the perinatal variables previously reported are predictive of early childhood outcome in this modern cohort of SGA infants.

Adult↗

PubMed2000

Predictive value of neonatal neurological tests for developmental outcome of preterm infants.

BACKGROUND: There is a need to identify, as early as possible, infants who are at risk for long-term neurological morbidity. METHODS: To predict neurodevelopment outcome of preterm infants <30 weeks' gestation in a population of 100 infants, we used several neonatal and neurobehavioral tests, including cranial ultrasonography, the Prechtl neurological test, quality of spontaneous general movements, and quality of sleep-wake organization. RESULTS: The Prechtl test at corrected term age and findings on cranial sonograms both had high specificity, but the Prechtl test had better overall positive predictive power for normal neurological and developmental outcomes at 2 years' corrected age. Developmental changes in sleep and the amount of indeterminate sleep did not correlate with outcome. Scoring general movement quality did not predict outcome and did not augment the positive predictive power of the Prechtl test. CONCLUSIONS: The Prechtl test at corrected term age (independent of the other tests) is the best positive predictor of normal neurological outcome and Bayley test results at 2 years' corrected age.

Developmental Disabilities↗

PubMed2001

Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency.

OBJECTIVE: The objective was to evaluate the cognitive, behavioral, and neurodevelopmental function in patients with adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) and to compare the findings with those of a case control group of patients without ADA-SCID. STUDY DESIGN: Case-matched pairs of patients with ADA-SCID (n = 11) and patients without ADA-SCID who had undergone bone marrow transplantation were recruited. Subjects were assessed by age-appropriate standard tests of intelligence, behavior, and neurodevelopment. RESULTS: Cognitive ability was not significantly different between the 2 groups, but patients with ADA-SCID showed a significant inverse correlation between deoxyadenosinetrisphosphate levels at diagnosis and IQ (P =.048). Behavioral assessment showed that patients with ADA-SCID functioned in the pathologic range on all domains, whereas mean scores for the control group were within normal limits. Behavioral impairment in patients with ADA-SCID also showed a significant positive correlation with age (P =.026). CONCLUSIONS: Cognitive function in ADA deficiency is adversely affected by the severity of metabolic derangement at the time of diagnosis. In addition, patients with ADA-SCID have significant behavioral abnormalities after transplantation. These defects are not due to the transplant procedure but reflect the systemic nature of ADA deficiency. These findings have important implications for future medical and nonmedical management strategies.

Adenosine Deaminase↗

PubMed2002

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide.

OBJECTIVE: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). STUDY DESIGN: Term infants with PPHN and a baseline oxygenation index of 24 +/- 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at approximately 1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. RESULTS: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. CONCLUSIONS: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups.

Administration, Inhalation↗

PubMed2002

Neurodevelopmental outcomes after biventricular repair of congenital heart defects.

OBJECTIVE: This study was undertaken to assess neurodevelopment of children after biventricular repair of congenital heart defects. METHODS: Full-scale, performance, and verbal IQs of 69 patients who had undergone biventricular repair were assessed at 5 years of age with the Wechsler Preschool and Primary Scales of Intelligence-Revised. The Wide Range Assessment of Visual-Motor Abilities was used to measure visual-motor skills. Regression analyses adjusting for parental IQ and socioeconomic status were used to evaluate outcome predictors. RESULTS: Median age at repair was 91 days (range 1-1558 days). Hypothermic circulatory arrest was used in 35 cases (mean duration of hypothermic circulatory arrest 33 +/- 17 minutes). Mean full-scale, performance, and verbal IQs for the entire study population were within the reference range (full-scale 96.9 +/- 15.9, performance 96.6 +/- 16.8, verbal 97.7 +/- 15.2). Anatomic diagnosis, age at operation, and use of hypothermic circulatory arrest did not influence full-scale IQ (P =.66, P =.14, and P =.46, respectively), performance IQ (P =.64, P =.36, and P =.73, respectively), or verbal IQ (P =.74, P =.08, and P =.39, respectively). Among patients subjected to hypothermic circulatory arrest, duration of arrest was evaluated as a predictor of outcome. After adjustment for parental IQ, full-scale (P =.12), performance (P =.07), and verbal (P =.22) IQ scores of patients with more than 39 minutes of hypothermic circulatory arrest were not different from those of patients who had arrest periods of 39 minutes or less. After adjustment for socioeconomic status, however, full-scale (P =.05) and performance (P =.03) IQ scores were lower among patients who had more than 39 minutes of hypothermic circulatory arrest. After adjustment for either parental IQ or socioeconomic status, patients with more than 39 minutes of arrest had lower scores on Wide Range Assessment of Visual-Motor Abilities subtests of visual-motor and fine motor abilities and on several performance IQ subtests. CONCLUSIONS: IQs of patients who had undergone biventricular repair of congenital heart defects were within the reference range. However, hypothermic circulatory arrest for longer than 39 minutes was associated with deficits in visual-motor and fine motor skills and possibly in full-scale IQ.

Boston↗

PubMed2003

Fetal myelomeningocele repair: short-term clinical outcomes.

OBJECTIVE: The study was undertaken to evaluate short-term clinical outcomes with antenatal myelomeningocele (MMC) repair. STUDY DESIGN: Retrospective review of 50 fetuses that underwent open fetal MMC closure was performed. Inclusion criteria included less than 26 weeks' gestation, thoracic to S1 level defect, absent clubfoot deformity, Arnold-Chiari malformation, ventriculomegaly less than 17 mm, normal karyotype, and no other anomalies. RESULTS: Perinatal survival was 94% (47/50 fetuses). Mean age at delivery was 34 weeks 3 days. All fetuses demonstrated reversal of hindbrain herniation. Forty-three percent of the 50 fetuses have required ventriculoperitoneal shunting compared with 100% thoracic, 88% lumbar, and 68% sacral (85% overall) in 297 historic controls. Better-than-predicted leg function was seen in 57% of thoracic and lumbar level lesion patients. CONCLUSION: Early experience with fetal MMC repair suggests a decreased need for ventriculoperitoneal shunting, arrest or slowing of progressive ventriculomegaly, and consistent resolution of hindbrain herniation. However, further long-term follow-up is needed to evaluate neurodevelopment and bladder and bowel function.

Adult↗

PubMed2003

Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome.

OBJECTIVE: To study the significance of growth status at birth and postnatal growth on neurodevelopmental outcome in very low birth weight (VLBW) infants. STUDY DESIGN: Growth and neurodevelopment were examined in 219 VLBW (<1250 g) children, 94 small for gestational age (SGA) (<10th percentile) and 125 appropriate for gestational age (AGA) (>10th percentile). Outcome at age 2 was assessed with the Bayley Scales of Infant Development (Mental Developmental Index [MDI], Psychomotor Developmental Index [PDI]) and a standardized neurologic examination. RESULTS: SGA status was not associated with poor neurodevelopmental outcome. However, after adjustment for covariables including cerebral palsy (CP), SGA children with weight <10th percentile at age 2 had lower mean PDI than SGA children with catch-up growth to weight >10th percentile (mean [SD], 89.9 [17.4] versus 101.8 [14.5]; P<.001). AGA children with catch-down growth (weight <10th percentile at age 2) were, independent of CP, more likely to have lower mean MDI (94.9 vs 101.7, P=.05) and PDI (81.9 vs 95.1; P<.001) than AGA children remaining >10th percentile at age 2. They also more frequently had severe CP (22.9% vs 1.2%; P=.008). CONCLUSIONS: In VLBW children, the course of postnatal growth rather than the appropriateness of weight for gestational age at birth determines later neurodevelopmental outcome.

Body Weight↗

PubMed2005

Fluoxetine during pregnancy: impact on fetal development.

Women are at greatest risk of suffering from depression during the childbearing years and thus may either become pregnant while taking an antidepressant or may require a prescription for one during pregnancy. The antidepressant fluoxetine (FX) is a selective serotonin reuptake inhibitor (SSRI), which increases serotonin neurotransmission. Serotonin is involved in the regulation of a variety of physiological systems, including the sleep-wake cycle, circadian rhythms and the hypothalamic-pituitary-adrenal axis. Each of these systems also plays an important role in fetal development. Compared with other antidepressant drugs, the SSRIs, such as FX, have fewer side effects. Because of this, they are now frequently prescribed, especially during pregnancy. Clinical studies suggest poor neonatal outcome after exposure to FX in utero. Recent studies in the sheep fetus describe the physiological effects of in utero exposure to FX with an 8 day infusion during late gestation in the sheep. This is a useful model for determining the effects of FX on fetal physiology. The fetus can be studied for weeks in its normal intrauterine environment with serial sampling of blood, thus permitting detailed studies of drug disposition in both mother and fetus combined with monitoring of fetal behavioural state and cardiovascular function. Fluoxetine causes an acute increase in plasma serotonin levels, leading to a transient reduction in uterine blood flow. This, in turn, reduces the delivery of oxygen and nutrients to the fetus, thereby presenting a mechanism for reducing growth and/or eliciting preterm delivery. Moreover, because FX crosses the placenta, the fetus is exposed directly to FX, as well as to the effects of the drug on the mother. Fluoxetine increases high-voltage/non-rapid eye movement behavioural state in the fetus after both acute and chronic exposure and, thus, may interfere with normal fetal neurodevelopment. Fluoxetine also alters hypothalamic function in the adult and increases the magnitude of the prepartum rise in fetal cortisol concentrations in sheep. Fetal FX exposure does not alter fetal circadian rhythms in melatonin or prolactin. Studies of the effects of FX exposure on fetal development in the sheep are important in defining possible physiological mechanisms that explain human clinical studies of birth outcomes after FX exposure. To date, there have been insufficient longer-term follow-up studies in any precocial species of offspring exposed to SSRIs in utero. Thus, further investigation of the long-term consequences of in utero exposure to FX and other SSRIs, as well as the mechanisms involved, are required for a complete understanding of the impact of these agents on development. This should involve studies in both humans and appropriate animal models.

Animals↗

PubMed2006

The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission.

Communication between neurons is largely achieved through chemical synapses, where neurotransmitters are released from synaptic vesicles at presynaptic terminals to activate postsynaptic cells. Exo- and endocytosis are coordinated to replenish the synaptic vesicle pool for sustained neuronal activity. We identified syd-9 (syd, synapse defective), a gene that encodes multiple C2H2 zinc-finger domain-containing proteins specifically required for synaptic function in Caenorhabditis elegans. syd-9 loss-of-function mutants exhibit locomotory defects, a diffuse distribution of synaptic proteins, and decreased synaptic transmission with unaffected neurodevelopment. syd-9 mutants share phenotypic and ultrastructural characteristics with mutants that lack synaptic proteins that are required for endocytosis. syd-9 mutants also display genetic interactions with these endocytotic mutants, suggesting that SYD-9 regulates endocytosis. SYD-9 proteins are enriched in the nuclei of both neuron and muscle cells, but their neuronal expression plays a major role in locomotion. SYD-9 isoforms display a speckle-like expression pattern that is typical of RNA-binding proteins that regulate premRNA splicing. Furthermore, syd-9 functions in parallel with unc-75 (unc, uncoordinated), the C. elegans homologue of the CELF/BrunoL family protein that regulates mRNA alternative splicing and processing, and is also required specifically for synaptic transmission. We propose that neuronal SYD-9 proteins are previously uncharacterized and specific posttranscriptional regulators of synaptic vesicle endocytosis.

Animals↗

PubMed2003

The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.

Triple A syndrome is a human autosomal recessive disorder characterized by an unusual array of tissue-specific defects. Triple A syndrome arises from mutations in a WD-repeat protein of unknown function called ALADIN (also termed Adracalin or AAAS). We showed previously that ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport. Here, we present evidence indicating that NPC targeting is essential for the function of ALADIN. Characterization of mutant ALADIN proteins from triple A patients revealed a striking effect of these mutations on NPC targeting. A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm. Microscopic analysis of cells from a triple A patient revealed no morphological abnormalities of the nuclei, nuclear envelopes, or NPCs. Importantly, these findings indicate that defects in NPC function, rather than structure, give rise to triple A syndrome. We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues. Our findings provide a foundation for understanding the molecular basis of triple A syndrome and may lead to unique insights into the role of nucleocytoplasmic transport in adrenal function and neurodevelopment.

Active Transport, Cell Nucleus↗

PubMed2000

Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody.

Reelin is a key mediator of ordered neuronal alignment in the brain. Here, we demonstrate that Reelin molecules assemble with each other to form a huge protein complex both in vitro and in vivo. The Reelin-Reelin interaction clearly is inhibited by the function-blocking anti-Reelin antibody, CR-50, at a concentration known to inhibit Reelin function. This assembly is mediated by electrostatic interaction of the CR-50 epitope region. Recombinant CR-50 epitope fragments spontaneously constitute a soluble, string-like homopolymer with a regularly repeated structure composed of more than 40 monomers. Mutated Reelin, which lacks the CR-50 epitope region, cannot form a homopolymer and fails to induce efficient tyrosine phosphorylation of Disabled 1 (Dab1), which should occur to transduce the Reelin signal. These data suggest that Reelin exerts its biological function by composing a large protein assembly driven by the CR-50 epitope region, proposing a novel model of the Reelin signaling in neurodevelopment.

Animals↗

PubMed2026

Loss of function of the chromatin remodeling gene INO80D leads to neurogenic features of schizophrenia.

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Humans↗

PubMed1985

Cerebellin: a quantifiable marker for Purkinje cell maturation.

The cerebellum-specific hexadecapeptide cerebellin has been localized by immunocytochemical means to the perikarya and dendrites of cerebellar Purkinje cells. Biochemical analysis using ion-pairing HPLC shows cerebellin to first appear 5 days after birth, whereafter levels rise to a maximum at 25 days postpartum, and then decline to stable adult values. This same pattern of development occurs with a lag of approximately 5 days for the major metabolite of cerebellin, des-Ser1-cerebellin. The immunocytochemical picture of cerebellin in developing Purkinje cells mirrors the biochemical data. These results show that cerebellins represent unique quantifiable markers for the investigation of Purkinje cell maturation and lend support to the feasibility of using unique endogenous peptides to chart neurodevelopment.

Aging↗

PubMed1997

Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.

G protein-gated, inwardly rectifying K+ channels (GIRK) are effectors of G protein-coupled receptors for neurotransmitters and hormones and may play an important role in the regulation of neuronal excitability. GIRK channels may be important in neurodevelopment, as suggested by the recent finding that a point mutation in the pore region of GIRK2 (G156S) is responsible for the weaver (wv) phenotype. The GIRK2 G156S gene gives rise to channels that exhibit a loss of K+ selectivity and may also exert dominant-negative effects on G(betagamma)-activated K+ currents. To investigate the physiological role of GIRK2, we generated mutant mice lacking GIRK2. Unlike wv/wv mutant mice, GIRK2 -/- mice are morphologically indistinguishable from wild-type mice, suggesting that the wv phenotype is likely due to abnormal GIRK2 function. Like wv/wv mice, GIRK2 -/- mice have much reduced GIRK1 expression in the brain. They also develop spontaneous seizures and are more susceptible to pharmacologically induced seizures using a gamma-aminobutyric acid antagonist. Moreover, wv/- mice exhibit much milder cerebellar abnormalities than wv/wv mice, indicating a dosage effect of the GIRK2 G156S mutation. Our results indicate that the weaver phenotypes arise from a gain-of-function mutation of GIRK2 and that GIRK1 and GIRK2 are important mediators of neuronal excitability in vivo.

Animals↗

PubMed1997

Ortho-substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain.

A stringent structure-activity relationship among polychlorinated biphenyls (PCBs) possessing two or more ortho-chlorine substituents is observed for activation of ryanodine receptors in mammalian brain, revealing an arylhydrocarbon receptor-independent mechanism through which non-coplanar PCBs disrupt neuronal Ca2+ signaling. Of the congeners assayed, non-coplanar PCB 95 exhibits the highest potency (EC50 = 12-24 microM) toward activating high affinity [3H]ryanodine-binding in rat hippocampus, cerebellum, and cerebral cortex. Coplanar PCB 66 and PCB 126 have no ryanodine receptor activity in all brain regions examined. PCB 95 enhances [3H]ryanodine-binding affinity and capacity by significantly altering modulation by Ca2+ and Mg2+, thereby stabilizing a high affinity conformation of the ryanodine receptor. Ca2+ transport measurements using cortical microsomes reveal that PCB 95 discriminates between inositol 1,4,5-trisphosphate- and ryanodine-sensitive stores. PCB 95 selectively mobilizes Ca2+ from ryanodine-sensitive stores in a dose-dependent manner (EC50 = 3.5 microM) and is completely inhibited by ryanodine receptor blockers, whereas coplanar PCBs are inactive. These data demonstrate that ortho-substituted PCBs disrupt Ca2+ transport in central neurons by direct interaction with ryanodine receptors, showing high selectivity and specificity. Alteration of Ca2+ signaling mediated by ryanodine receptors in specific regions of the central nervous system may account, at least in part, for the significant impact of these agents toward neurodevelopment and neuroplasticity in mammals.

Animals↗

PubMed2000

Functional mapping of receptor specificity domains of glial cell line-derived neurotrophic factor (GDNF) family ligands and production of GFRalpha1 RET-specific agonists.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (GDNF, neurturin, artemin, and persephin) are critical regulators of neurodevelopment and support the survival of midbrain dopaminergic and spinal motor neurons in vitro and in animal disease models making them attractive therapeutic candidates for treatment of neurodegenerative diseases. The GFLs signal through a multicomponent receptor complex comprised of a high affinity binding component (GDNF-family receptor alpha-component (GFRalpha1-GFRalpha4)) and the receptor tyrosine kinase RET. To begin characterization of GFL receptor specificity at the molecular level, we performed comprehensive homologue-scanning mutagenesis of GDNF, the prototypical member of the GFLs. Replacing short segments of GDNF with the homologous segments from persephin (PSPN) (which cannot bind or activate GFRalpha1.RET or GFRalpha2.RET) identified sites along the second finger of GDNF critical for activating the GFRalpha1.RET and GFRalpha2.RET receptor complexes. Furthermore, introduction of these regions from GDNF, neurturin, or artemin into PSPN demonstrated that they are sufficient for activating GFRalpha1. RET, but additional determinants are required for interaction with the other GFRalphas. This difference in the molecular basis of GFL-GFRalpha specificity allowed the production of GFRalpha1. RET-specific agonists and provides a foundation for understanding of GFL-GFRalpha.RET signaling at the molecular level.

3T3 Cells↗