ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish

The role of the ETS gene PEA3 in the development of motor and sensory neurons

To assess motor and mental development before and after strabismus surgery in children with infantile esotropia. Mental and motor development indexes of 20 children with infantile esotropia without neurologic abnormalities and 17 age-matched healthy control subjects were prospectively tested at regular intervals before and after strabismus surgery with the Dutch version of the Bayley and ordinal scales of infant development. The mean age for surgery in the study group was 13.5 months. Before strabismus surgery, the Bayley scales of infant development showed a significant delay in both mental (P < .045) and motor (P < .008) development for children with infantile esotropia compared with the control group. Three weeks after surgery, the delay in mental development had disappeared. The delay in motor development persisted for months. Two of the 7 ordinal scales--object permanence (P < .01) and means-end (P < .036)--showed a statistically significant delay for children with infantile esotropia. Three weeks after strabismus surgery, there was no difference between the study group and the control group. Children with infantile esotropia had delayed motor and mental development compared with healthy children. After strabismus surgery, patients recovered mentally, but their motor delays persisted for months when tested with the Bayley scales of infant development.

The Notch signaling pathway is essential for neuronal and glial specification during CNS development. Mind bomb-1 (Mib1) is an E3 ubiquitin ligase that ubiquitinates and promotes the endocytosis of Notch ligands. Although Mib1 is essential for transmitting the Notch signal, it is still unclear whether it is a primary regulator of Notch ligand activity in the developing spinal cord. In Mib1 conditional knock-out mice, we observed depletion of spinal progenitors, premature differentiation of neurons, and unbalanced specification of V2 interneurons, all of which mimic the conventional Notch phenotype. In agreement with this, the reduction of progenitors in the absence of Mib1 led to a loss of both astrocytes and oligodendrocytes. Late removal of Mib1 using a drug-inducible system suppressed glial differentiation, suggesting that Mib1 continues to play a role in the formation of late progenitors mainly designated for gliogenesis. Finally, misexpression of Mib1 or Mib1 deletion mutants revealed that the ring domain of Mib1 is required for the specification of V2 interneurons in the chick neural tube. Together, these findings suggest that Mib1 is a major component of the signal-sending cells required to provide Notch ligand activity for specifying neurons and glia in the spinal cord.

Di-butyl phthalate disrupts muscle, motor and sensory neuron development in embryonic zebrafish

Nexmif is mainly expressed in the central nervous system (CNS) and plays important roles in cell migration, cell to cell and cell-matrix adhesion, and maintains normal synaptic formation and function. Nevertheless, it is unclear how nexmif is linked to motor neuron morphogenesis. Here, we provided in situ hybridization evidence that nexmifa (zebrafish paralog) was localized to the brain and spinal cord and acted as a vital regulator of motor neuron morphogenesis. Nexmifa deficiency in zebrafish larvae generated abnormal primary motor neuron (PMN) development, including truncated Cap axons and decreased branches in Cap axons. Importantly, RNA-sequencing showed that nexmifa-depleted zebrafish embryos caused considerable CNS related gene expression alterations. Differentially expressed genes (DEGs) were mainly involved in axon guidance and several synaptic pathways, including glutamatergic, GABAergic, dopaminergic, cholinergic, and serotonergic synapse pathways, according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation. In particular, when compared with other pathways, DEGs were highest (84) in the axon guidance pathway, according to Organismal Systems. Efna5b, bmpr2b, and sema6ba were decreased markedly in nexmifa-depleted zebrafish embryos. Moreover, both overexpression of efna5b mRNA and sema6ba mRNA could partially rescued motor neurons morphogenesis. These observations supported nexmifa as regulating axon morphogenesis of motor neurons in zebrafish. Taken together, nexmifa elicited crucial roles during motor neuron development by regulating the morphology of neuronal axons.

Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific Disease

Regulation of cholinergic expression in cultured spinal cord neurons

Novel mutations in MTERF3: First report of a new genetic cause in two Chinese patients with developmental delay, intermittent hypoglycemia and metabolic acidosis.

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

Section 1 Postural Control.- Postural Control and Development.- The Development of Proprioceptive Control.- Postural Control.- Section 2 Skill Development and Learning Disabilities.- Some Aspects of the Development of Motor Control in Down's Syndrome.- The Trainability of Motor Processing Strategies with Developmentally Delayed Performers.- Motor Dysfunctions in Children. Towards a Process-Oriented Diagnosis.- Information Processing and Motivation as Determinants of Performance in Children with Learning Disabilities.- Development of Coordination and Control in the Mentally Handicapped.- Manual Language: Its Relevance to Communication Acquisition in Autistic Children.- Section 3 The Development of Fine Motor Skills.- The Formation of the Finger Grip during Prehension a Cortically-Mediated Visuo-Motor Pattern.- Handwriting Disturbances: Developmental Trends.- Section 4 Perceptual and Cognitive Control of Motor Behaviour.- Normal and Abnormal Repetitive Stereotyped Behaviours.- Inhibitory Mechanisms in Children's Skill Development.- Sensory-Motor Control and Balance: A Behavioural Perspective.- Section 5 Posture and Locomotion.- From Stepping to Adaptive Walking: Modulations of an Automatism.- Developmental Changes in the Relative Timing of Locomotion.- Section 6 Cultural Influences.- Motor Development and Cultural Attitudes.- The Acquisition of an Everyday Technical Motor Skill: The Pounding of Cereals in Mali.- Section 7 Speech & Language.- Parallels between Motor and Language Development.- Lateralisation and Motor Development.- Author Index.

Neurotoxic effects of local anesthetics (LAs) on developing motor neurons have not been documented. We investigated the neurotoxic effects of LAs on developing motor neurons in terms of cell viability, cytotoxicity, reactive oxygen species (ROS), and apoptosis. Embryonic spinal cord motor neurons were isolated from Sprague-Dawley rat fetuses and exposed to one of the three LAs—lidocaine, bupivacaine, or ropivacaine—at concentrations of 1, 10, 100, or 1000 µM. The exposure duration was set to 1 or 24 h. The neurotoxic effects of LAs were determined by evaluating the following: cell viability, cytotoxicity, ROS production, and apoptosis. In the 1-h exposure group, the motor neurons exposed to lidocaine and bupivacaine had reduced cell viability and increased cytotoxicity, ROS, and apoptosis in a concentration-dependent manner. Lidocaine showed the highest toxicity, followed by bupivacaine. In the 24-h exposure group, all three LAs showed significant effects (decreased cell viability and increased cytotoxicity, ROS, and apoptosis) on the motor neurons in a concentration-dependent manner. The neurotoxic effects of lidocaine were greater than those of bupivacaine and ropivacaine. Ropivacaine appeared to have the least effect on motor neurons. This study identified the neurotoxic effects of lidocaine and bupivacaine on developing spinal cord motor neurons.

Ciliary neurotrophic factor is the first neurotrophic factor to show survival-promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary neurotrophic factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary neurotrophic factor (n = 6) resulted in delayed weight gain (p < 0.001), grip strength normalized to body weight in the factor-treated mice was significantly greater (p < 0.02) and declined at a slower rate (p < 0.05) compared to that in vehicle-treated animals. Human ciliary neurotrophic factor (n = 27) produced no change in body weight and reduced paw position and walking pattern abnormalities (p < 0.001 and p < 0.02, respectively). After 4 weeks of treatment, the mean grip strength of human ciliary neurotrophic factor-treated animals was twice as great (p < 0.001) and declined at a much slower rate (p < 0.005) than that of control mice. The time required to run 2.5 ft was less (p < 0.005) and muscle twitch tension was greater (p < 0.002) in ciliary neurotrophic factor-treated animals. Thus, ciliary neurotrophic factor retarded the disease progression and improved muscle strength in this motor neuron disease model.

Motor neuron (MN) development in early onset spasticity is poorly understood. For example, spastic cerebral palsy (sCP), the most common motor disability of childhood, is poorly predicted by brain imaging, yet research remains focused on the brain. By contrast, MNs, via the motor unit and neurotransmitter signaling, are the target of most therapeutic spasticity treatments and are the final common output of motor control. MN development in sCP is a critical knowledge gap, because the late embryonic and postnatal periods are not only when the supposed brain injury occurs but also are critical times for spinal cord neuromotor development. Using an animal model of early onset spasticity [ spa mouse (B6.Cg- Glrbspa/J) with a glycine (Gly) receptor mutation], we hypothesized that removal of effective glycinergic neurotransmitter inputs to MNs during development will influence MN pruning (including primary dendrites) and MN size. Spa (Glrb-/-) and wild-type (Glrb+/+) mice, ages 4-9 wk, underwent unilateral retrograde labeling of the tibialis anterior muscle MNs via peroneal nerve dip in tetramethylrhodamine. After 3 days, mice were euthanized and perfused with 4% paraformaldehyde, and the spinal cord was excised and processed for confocal imaging. Spa mice had ~61% fewer lumbar tibialis anterior MNs ( P < 0.01), disproportionately affecting larger MNs. Additionally, a ~23% reduction in tibialis anterior MN somal surface area ( P < 0.01) and a 12% increase in primary dendrites ( P = 0.046) were observed. Thus MN pruning and MN somal surface area are abnormal in early onset spasticity. Fewer and smaller MNs may contribute to the spastic phenotype. NEW & NOTEWORTHY Motor neuron (MN) development in early onset spasticity is poorly understood. In an animal model of early onset spasticity, spa mice, we found ~61% fewer lumbar tibialis anterior MNs compared with controls. This MN loss disproportionately affected larger MNs. Thus number and heterogeneity of the MN pool are decreased in spa mice, likely contributing to the spastic phenotype.

Mutations in copper-zinc superoxide dismutase (SOD1) have been linked to a subset of familial amytrophic lateral sclerosis (fALS), a fatal neurodegenerative disease characterized by progressive motor neuron death. An increasing amount of evidence supports that mitochondrial dysfunction and apoptosis activation play a critical role in the fALS etiology, but little is known about the mechanisms by which SOD1 mutants cause the mitochondrial dysfunction and apoptosis. In this study, we use proteomic approaches to identify the mitochondrial proteins that are altered in the presence of a fALS-causing mutant G93A-SOD1. A comprehensive characterization of mitochondrial proteins from NSC34 cells, a motor neuron-like cell line, was achieved by two independent proteomic approaches. Four hundred seventy unique proteins were identified in the mitochondrial fraction collectively, 75 of which are newly discovered proteins that previously had only been reported at the cDNA level. Two-dimensional gel electrophoresis was subsequently used to analyze the differences between the mitochondrial proteomes of NSC34 cells expressing wild-type and G93A-SOD1. Nine and 36 protein spots displayed elevated and suppressed abundance respectively in G93A-SOD1-expressing cells. The 45 spots were identified by MS, and they include proteins involved in mitochondrial membrane transport, apoptosis, the respiratory chain, and molecular chaperones. In particular, alterations in the post-translational modifications of voltage-dependent anion channel 2 (VDAC2) were found, and its relevance to regulating mitochondrial membrane permeability and activation of apoptotic pathways is discussed. The potential role of other proteins in the mutant SOD1-mediated fALS is also discussed. This study has produced a short list of mitochondrial proteins that may hold the key to the mechanisms by which SOD1 mutants cause mitochondrial dysfunction and neuronal death. It has laid the foundation for further detailed functional studies to elucidate the role of particular mitochondrial proteins, such as VDAC2, in the pathogenesis of familial ALS.

Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism. We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient's cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption. The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient's cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development. Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum. NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder. A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects. NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation. Zebrafish with ndufa3 knock down manifests delayed locomotor development. With this reported patient, the relationship between the gene and disease can be upgraded from "limited" to "moderate".