Nuclear architecture as an epigenetic regulator of neural development and function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

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Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

Cell Death and Disease ◽

10.1038/s41419-021-03687-8 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Peng Chen ◽

Hongyang Jing ◽

Mingtao Xiong ◽

Qian Zhang ◽

Dong Lin ◽

...

Keyword(s):

Neural Development ◽

Protein Level ◽

Brain Regions ◽

Postmortem Brain ◽

Pathophysiological Mechanism ◽

Brain Disorders ◽

Spine Density ◽

Genes Encoding ◽

High Level ◽

And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

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MicroRNAs Regulate Multiple Aspects of Locomotor Behavior in Drosophila

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400793 ◽

2019 ◽

Vol 10 (1) ◽

pp. 43-55

Author(s):

Nathan C. Donelson ◽

Richa Dixit ◽

Israel Pichardo-Casas ◽

Eva Y. Chiu ◽

Robert T. Ohman ◽

...

Keyword(s):

Nervous System ◽

Neural Development ◽

Locomotor Behavior ◽

Temperature Dependent ◽

Motor Circuits ◽

The Many ◽

And Function ◽

Post Transcriptional Regulation ◽

Movement Tracking

Locomotion is an ancient and fundamental output of the nervous system required for animals to perform many other complex behaviors. Although the formation of motor circuits is known to be under developmental control of transcriptional mechanisms that define the fates and connectivity of the many neurons, glia and muscle constituents of these circuits, relatively little is known about the role of post-transcriptional regulation of locomotor behavior. MicroRNAs have emerged as a potentially rich source of modulators for neural development and function. In order to define the microRNAs required for normal locomotion in Drosophila melanogaster, we utilized a set of transgenic Gal4-dependent competitive inhibitors (microRNA sponges, or miR-SPs) to functionally assess ca. 140 high-confidence Drosophila microRNAs using automated quantitative movement tracking systems followed by multiparametric analysis. Using ubiquitous expression of miR-SP constructs, we identified a large number of microRNAs that modulate aspects of normal baseline adult locomotion. Addition of temperature-dependent Gal80 to identify microRNAs that act during adulthood revealed that the majority of these microRNAs play developmental roles. Comparison of ubiquitous and neural-specific miR-SP expression suggests that most of these microRNAs function within the nervous system. Parallel analyses of spontaneous locomotion in adults and in larvae also reveal that very few of the microRNAs required in the adult overlap with those that control the behavior of larval motor circuits. These screens suggest that a rich regulatory landscape underlies the formation and function of motor circuits and that many of these mechanisms are stage and/or parameter-specific.

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Childhood Adversity and Neural Development: A Systematic Review

Annual Review of Developmental Psychology ◽

10.1146/annurev-devpsych-121318-084950 ◽

2019 ◽

Vol 1 (1) ◽

pp. 277-312 ◽

Cited By ~ 32

Author(s):

Katie A. McLaughlin ◽

David Weissman ◽

Debbie Bitrán

Keyword(s):

Systematic Review ◽

Neural Development ◽

Childhood Adversity ◽

Hippocampal Volume ◽

Extensive Literature ◽

Dimensional Model ◽

Neural Structure ◽

The Past ◽

Acceleration Model ◽

And Function

An extensive literature on childhood adversity and neurodevelopment has emerged over the past decade. We evaluate two conceptual models of adversity and neurodevelopment—the dimensional model of adversity and stress acceleration model—in a systematic review of 109 studies using MRI-based measures of neural structure and function in children and adolescents. Consistent with the dimensional model, children exposed to threat had reduced amygdala, medial prefrontal cortex (mPFC), and hippocampal volume and heightened amygdala activation to threat in a majority of studies; these patterns were not observed consistently in children exposed to deprivation. In contrast, reduced volume and altered function in frontoparietal regions were observed consistently in children exposed to deprivation but not children exposed to threat. Evidence for accelerated development in amygdala-mPFC circuits was limited but emerged in other metrics of neurodevelopment. Progress in charting neurodevelopmental consequences of adversity requires larger samples, longitudinal designs, and more precise assessments of adversity.

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Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1411269112 ◽

2015 ◽

Vol 112 (22) ◽

pp. 6800-6806 ◽

Cited By ~ 129

Author(s):

Benyam Kinde ◽

Harrison W. Gabel ◽

Caitlin S. Gilbert ◽

Eric C. Griffith ◽

Michael E. Greenberg

Keyword(s):

Dna Methylation ◽

Binding Protein ◽

Cell Types ◽

Cpg Methylation ◽

Early Postnatal Development ◽

Cpg Dinucleotides ◽

Epigenetic Regulator ◽

And Function ◽

Syndrome Protein ◽

The Brain

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.

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Wnt Signaling in Vertebrate Neural Development and Function

Journal of Neuroimmune Pharmacology ◽

10.1007/s11481-012-9404-x ◽

2012 ◽

Vol 7 (4) ◽

pp. 774-787 ◽

Cited By ~ 66

Author(s):

Kimberly A. Mulligan ◽

Benjamin N. R. Cheyette

Keyword(s):

Wnt Signaling ◽

Neural Development ◽

And Function

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MAP1 structural organization in Drosophila: in vivo analysis of FUTSCH reveals heavy- and light-chain subunits generated by proteolytic processing at a conserved cleavage site

Biochemical Journal ◽

10.1042/bj20071449 ◽

2008 ◽

Vol 414 (1) ◽

pp. 63-71 ◽

Cited By ~ 9

Author(s):

Beiyan Zou ◽

Huaru Yan ◽

Fumiko Kawasaki ◽

Richard W. Ordway

Keyword(s):

Light Chain ◽

Neural Development ◽

Cleavage Site ◽

Structural Organization ◽

Single Gene ◽

Proteolytic Cleavage ◽

Proteolytic Processing ◽

In Vivo Analysis ◽

And Function

The MAP1 (microtubule-associated protein 1) family is a class of microtubule-binding proteins represented by mammalian MAP1A, MAP1B and the recently identified MAP1S. MAP1A and MAP1B are expressed in the nervous system and thought to mediate interactions of the microtubule-based cytoskeleton in neural development and function. The characteristic structural organization of mammalian MAP1s, which are composed of heavy- and light-chain subunits, requires proteolytic cleavage of a precursor polypeptide encoded by the corresponding map1 gene. MAP1 function in Drosophila appears to be fulfilled by a single gene, futsch. Although the futsch gene product is known to share several important functional properties with mammalian MAP1s, whether it adopts the same basic structural organization has not been addressed. Here, we report the identification of a Drosophila MAP1 light chain, LCf, produced by proteolytic cleavage of a futsch-encoded precursor polypeptide, and confirm co-localization and co-assembly of the heavy chain and LCf cleavage products. Furthermore, the in vivo properties of MAP1 proteins were further defined through precise MS identification of a conserved proteolytic cleavage site within the futsch-encoded MAP1 precursor and demonstration of light-chain diversity represented by multiple LCf variants. Taken together, these findings establish conservation of proteolytic processing and structural organization among mammalian and Drosophila MAP1 proteins and are expected to enhance genetic analysis of conserved MAP1 functions within the neuronal cytoskeleton.

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Embryonic exposure to benzo(a)pyrene influences neural development and function in rockfish (Sebastiscus marmoratus)

NeuroToxicology ◽

10.1016/j.neuro.2012.01.002 ◽

2012 ◽

Vol 33 (4) ◽

pp. 758-762 ◽

Cited By ~ 21

Author(s):

Chengyong He ◽

Chonggang Wang ◽

Yulin Zhou ◽

Jian Li ◽

Zhenghong Zuo

Keyword(s):

Neural Development ◽

Embryonic Exposure ◽

Sebastiscus Marmoratus ◽

And Function

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Using zebrafish to assess the impact of drugs on neural development and function

Expert Opinion on Drug Discovery ◽

10.1517/17460440902988464 ◽

2009 ◽

Vol 4 (7) ◽

pp. 715-726 ◽

Cited By ~ 80

Author(s):

Su Guo

Keyword(s):

Neural Development ◽

And Function ◽

The Impact

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Pairing your Sox: Identification of Sox11 partner proteins and interaction domains in the developing neural plate

10.1101/2020.04.23.057919 ◽

2020 ◽

Author(s):

Kaela S. Singleton ◽

Pablo Silva-Rodriguez ◽

Elena M. Silva

Keyword(s):

Protein Interactions ◽

Neural Development ◽

Specific Protein ◽

Neural Plate ◽

Neural Fate ◽

Mouse Cortex ◽

Interaction Domains ◽

Species Specific ◽

And Function ◽

Partner Proteins

AbstractSox11, a member of the SoxC family of transcription factors, has distinct functions at different times in neural development. Studies in mouse, frog, chick and zebrafish show that Sox11 promotes neural fate, neural differentiation, and neuron maturation in the central nervous system. These diverse roles are controlled in part by spatial and temporal-specific protein interactions. However, the partner proteins and Sox11-interaction domains underlying these diverse functions are not well defined. Here, we identify partner proteins and the domains of Xenopus Sox11(xSox11) required for protein interaction and function during neurogenesis. Our data show that Sox11 co-localizes and interacts with Pou3f2 and Ngn2 in the anterior neural plate and in early neurons, respectively. We also demonstrate that xSox11 does not interact with Ngn1, a high affinity partner of Sox11 in the mouse cortex, suggesting that Sox11 has species-specific partner proteins. Additionally, we determined that the N-terminus including the HMG domain of xSox11 is necessary for interaction with Pou3f2 and Ngn2, and established a novel role for the N-terminal 46 amino acids in the establishment of placodal progenitors. This is the first identification of partner proteins for Xenopus Sox11 and of domains required for partner protein interactions and distinct roles in neurogenesis.

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