Correlative biochemical and morphological studies of myelination in human ontogenesis

Niebrój-Dobosz, I; Fidziańska, Anna; Rafałowska, J; Sawicka, Ewa

doi:10.1007/bf00690755

Cited by 16 publications

(11 citation statements)

References 11 publications

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“…Axons of this morphology were very rarely seen in control VRs, even as early as 1 day of life (fig. S3, R and T), but are well documented in human fetal nerve (21,22). This preponderance of directly abutting axons was also found in SMA intercostal nerves (fig.…”

Section: Impaired Development and Degeneration Of Human Sma Motor Neu...mentioning

confidence: 57%

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

et al. 2021

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Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

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Section: Impaired Development and Degeneration Of Human Sma Motor Neu...mentioning

confidence: 57%

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

et al. 2021

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“…2G). Myelination occurs earlier in motor than sensory roots (Niebroj-Dobosz et al, 1980), and expression of myelin-specific mRNAs is detectable at P1 in motor but not sensory roots (Baron et al, 1994;Forghani et al, 2001). Thus, to correlate the onset of DG with the beginning of myelination, we stained motor and sensory roots at P1.…”

Section: The Expression Of Dg Briefly Precedes and Parallels Myelinatmentioning

confidence: 99%

Expression of Laminin Receptors in Schwann Cell Differentiation: Evidence for Distinct Roles

Previtali¹,

Nodari²,

Taveggia³

et al. 2003

J. Neurosci.

119

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Schwann cells require laminin-2 throughout nerve development, because mutations in the alpha2 chain in dystrophic mice interfere with sorting of axons before birth and formation of myelin internodes after birth. Mature Schwann cells express several laminin receptors, but their expression and roles in development are poorly understood. Therefore, we correlated the onset of myelination in nerve and synchronized myelinating cultures to the appearance of integrins and dystroglycan in Schwann cells. Only alpha6beta1 integrin is expressed before birth, whereas dystroglycan and alpha6beta4 integrin appear perinatally, just before myelination. Although dystroglycan is immediately polarized to the outer surface of Schwann cells, alpha6beta4 appears polarized only after myelination. We showed previously that Schwann cells lacking beta1 integrin do not relate properly to axons before birth. Here we show that the absence of beta1 before birth is not compensated by other laminin receptors, whereas coexpression of both dystroglycan and beta4 integrin is likely required for beta1-null Schwann cells to myelinate after birth. Finally, both beta1-null and dystrophic nerves contain bundles of unsorted axons, but they are predominant in different regions: in spinal roots in dystrophic mice and in nerves in beta1-null mice. We show that differential compensation by laminin-1, but not laminin receptors may partially explain this. These data suggest that the action of laminin is mediated by beta1 integrins during axonal sorting and by dystroglycan, alpha6beta1, and alpha6beta4 integrins during myelination.

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“…Literature data show that myelination usually begins when axons have reached a caliber of about 1 m, so that those Þbers that are the Þrst to be myelinated correspond to the largest Þbers in mature nerves [24]. Moreover, myelination of motor roots is known to precede that of sensory ones [32]. Therefore, nerve Þbers which Þrst undergo myelination and mostly represent motor axons could have been mainly affected by prenatal CO exposure.…”

Section: Discussionmentioning

confidence: 99%

Prenatal exposure to low levels of carbon monoxide alters sciatic nerve myelination in rat offspring

et al. 2000

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Correlative biochemical and morphological studies of myelination in human ontogenesis

Cited by 16 publications

References 11 publications

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

Expression of Laminin Receptors in Schwann Cell Differentiation: Evidence for Distinct Roles

Prenatal exposure to low levels of carbon monoxide alters sciatic nerve myelination in rat offspring

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