RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development

Dhananjaya, D; Hung, Kuan-Yang; Tarn, Woan‐Yuh

doi:10.1128/mcb.00007-18

Cited by 21 publications

(5 citation statements)

References 31 publications

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“…While Ptbp1 promotes exclusion of exons 7/8 early during neocortical development, Rbm4 governs their inclusion during mid developmental stages, generating a full-length Dab1 isoform that predominates during migration of later-born neurons. This splicing switch enables phosphorylation of the tyrosine residues of exons 7/8 in response to Reelin signaling, which subsequently activates cytoskeletal machinery and coordinates directional migration (Dhananjaya et al, 2018).…”

Section: Establishment Of the Unique Layered Structure Of The Neocortexmentioning

confidence: 99%

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

Salamon

Rašin

2022

Front. Neurosci.

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The human neocortex is undoubtedly considered a supreme accomplishment in mammalian evolution. It features a prenatally established six-layered structure which remains plastic to the myriad of changes throughout an organism’s lifetime. A fundamental feature of neocortical evolution and development is the abundance and diversity of the progenitor cell population and their neuronal and glial progeny. These evolutionary upgrades are partially enabled due to the progenitors’ higher proliferative capacity, compartmentalization of proliferative regions, and specification of neuronal temporal identities. The driving force of these processes may be explained by temporal molecular patterning, by which progenitors have intrinsic capacity to change their competence as neocortical neurogenesis proceeds. Thus, neurogenesis can be conceptualized along two timescales of progenitors’ capacity to (1) self-renew or differentiate into basal progenitors (BPs) or neurons or (2) specify their fate into distinct neuronal and glial subtypes which participate in the formation of six-layers. Neocortical development then proceeds through sequential phases of proliferation, differentiation, neuronal migration, and maturation. Temporal molecular patterning, therefore, relies on the precise regulation of spatiotemporal gene expression. An extensive transcriptional regulatory network is accompanied by post-transcriptional regulation that is frequently mediated by the regulatory interplay between RNA-binding proteins (RBPs). RBPs exhibit important roles in every step of mRNA life cycle in any system, from splicing, polyadenylation, editing, transport, stability, localization, to translation (protein synthesis). Here, we underscore the importance of RBP functions at multiple time-restricted steps of early neurogenesis, starting from the cell fate transition of transcriptionally primed cortical progenitors. A particular emphasis will be placed on RBPs with mostly conserved but also divergent evolutionary functions in neural progenitors across different species. RBPs, when considered in the context of the fascinating process of neocortical development, deserve to be main protagonists in the story of the evolution and development of the neocortex.

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Section: Establishment Of the Unique Layered Structure Of The Neocortexmentioning

confidence: 99%

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

Salamon

Rašin

2022

Front. Neurosci.

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“…The RNA binding protein RBM4 modulates precursor mRNA splicing and mRNA translation. Depletion of RBM4 impairs the differentiation of various cell types, including neuronal cells 1 – 6 . RBM4 promotes neuronal differentiation by modulating alternative splicing of the cell-fate determinant Numb and the glycolytic enzyme pyruvate kinase M 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

“…RBM4 promotes neuronal differentiation by modulating alternative splicing of the cell-fate determinant Numb and the glycolytic enzyme pyruvate kinase M 4 , 5 . Moreover, an in-utero experiment demonstrated that RBM4 participates in radial migration of newborn neurons in the developing cerebral cortex by promoting the expression of full-length Dab1 6 , a regulator of Reelin signaling that controls neuronal positioning. However, whether RBM4 is essential for brain development has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency

Tsai,

Shen,

et al. 2023

Commun Biol

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A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation—the intercrural fissure in particular—in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency.

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“…Alternative splicing (AS) is one of the major molecular processes underlying increased transcriptome and proteome diversity and associated organismal complexity in metazoans [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

Roles of developmentally regulated KIF2A alternative isoforms in cortical neuron migration and differentiation

et al. 2021

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KIF2A is a kinesin motor protein with essential roles in neural progenitor division and axonal pruning during brain development. However, how different KIF2A alternative isoforms function during development of the cerebral cortex is not known. Here, we focus on three Kif2a isoforms expressed in the developing cortex. We show that Kif2a is essential for dendritic arborization in mice and that the functions of all three isoforms are sufficient for this process. Interestingly, only two of the isoforms can sustain radial migration of cortical neurons while a third isoform, lacking a key N-terminal region, is ineffective. By proximity-based interactome mapping for individual isoforms, we identify previously known KIF2A interactors, proteins localized to the mitotic spindle poles, and unexpectedly, also translation factors, ribonucleoproteins and proteins that are targeted to organelles, prominently to the mitochondria. In addition, we show that a KIF2A mutation, which causes brain malformations in humans, has extensive changes to its proximity-based interactome, with depletion of mitochondrial proteins identified in the wild-type KIF2A interactome. Our data raises new insights about the importance of alternative splice variants during brain development.

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RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development

Cited by 21 publications

References 31 publications

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation

Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency

Roles of developmentally regulated KIF2A alternative isoforms in cortical neuron migration and differentiation

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