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Developmentally upregulated transcriptional elongation factor a like 3 suppresses axon regeneration after optic nerve injury.

ABSTRACT: Projection neurons of the mammalian central nervous system (CNS) do not spontaneously regenerate axons which have been damaged by an injury or disease, often leaving patients with permanent disabilities that affect motor, cognitive, or sensory functions. Although several molecular targets which promote some extent of axon regeneration in animal models have been identified, the resulting recovery is very limited, and the molecular mechanisms underlying the axonal regenerative failure in the CNS are still poorly understood. One of the most studied targets for axon regeneration in the CNS is the mTOR pathway. A number of developmentally regulated genes also have been found to play a role in CNS axon regeneration. Here, we found that Transcriptional Elongation Factor A Like 3 (Tceal3), belonging to the Bex/Tceal transcriptional regulator family, which also modulates the mTOR pathway, is developmentally upregulated in retinal ganglion cell (RGCs) projection CNS neurons, and suppresses their capacity to regenerate axons after injury.

SUBMITTER: Lukomska A

PROVIDER: S-EPMC8572158 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Developmentally upregulated transcriptional elongation factor a like 3 suppresses axon regeneration after optic nerve injury.

Lukomska Agnieszka A Kim Juhwan J Rheaume Bruce A BA Xing Jian J Hoyt Alexela A Lecky Emmalyn E Steidl Tyler T Trakhtenberg Ephraim F EF

Neuroscience letters 20210921

Projection neurons of the mammalian central nervous system (CNS) do not spontaneously regenerate axons which have been damaged by an injury or disease, often leaving patients with permanent disabilities that affect motor, cognitive, or sensory functions. Although several molecular targets which promote some extent of axon regeneration in animal models have been identified, the resulting recovery is very limited, and the molecular mechanisms underlying the axonal regenerative failure in the CNS a ...[more]

PMID: 34560191

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Project description:BackgroundAxon regeneration within the mammalian central nervous system is extremely limited. In optic neuropathy conditions like glaucoma, the inability of retinal ganglion cell (RGC) axons to regenerate is a major impediment to functional recovery. In contrast, adult teleost fish such as zebrafish can fully regenerate RGC axons enabling visual recovery from optic nerve (ON) injury making it an ideal model to probe the mechanisms of successful axon regeneration.MethodsLaser Capture Microdissection followed by RNA-sequencing (LCM-seq) was used to identify genes and pathways differentially expressed in RGCs during ON regeneration. We validate these findings by in situ hybridization and qRT-PCR. Using loss- and gain-of-function experiments we demonstrate the necessity of srebf2 for efficient ON regeneration and recovery of visual function. Finally, we use LCM-seq coupled with experimental manipulations to identify downstream srebf2 target genes and test the role of hmgcra/b and mevalonate in this process. Statistical analysis was performed using Student's t-test, two-way ANOVA, or repeated measures with appropriate post-hoc tests where applicable.ResultsLCM-seq comparison of uninjured versus 3-day post ON injury RGCs identified significant upregulation of the cholesterol synthesis pathway during axon regeneration. The master regulator of this pathway, the transcription factor srebf2, is upregulated throughout the regeneration phase. Chemical inhibition or morpholino-based gene knockdown of srebf2 decreased axon regeneration into the ON and optic tectum and delayed recovery of visual behavior over the course of normal optic nerve regeneration without causing a significant loss of RGCs. Constitutively active srebf2 can fully rescue axon regeneration and visual behavior losses caused by inhibition of endogenous srebf2 but does not accelerate regeneration compared to the control group. LCM-seq confirms the expected regulation of predicted srebf2 target genes after loss- or gain-of-function in vivo. Downstream of srebf2, hmgcra/b knockdown or simvastatin treatment delayed axon regeneration and this effect was rescued by supplemental mevalonate. Mevalonate treatment alone was sufficient to accelerate ON regeneration.ConclusionsThese results demonstrate that srebf2 and the downstream mevalonate synthesis pathway plays an important role in regulating efficient axon regeneration in the zebrafish visual system. Involvement of this pathway should be closely examined in failed mammalian ON regeneration.

Dataset Information

Developmentally upregulated transcriptional elongation factor a like 3 suppresses axon regeneration after optic nerve injury.

Publications

Developmentally upregulated transcriptional elongation factor a like 3 suppresses axon regeneration after optic nerve injury.

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