Up‐regulation of <scp>HP</scp>1γ expression during neuronal maturation promotes axonal and dendritic development in mouse embryonic neocortex

Oshiro, Hiroaki; Hirabayashi, Yusuke; Furuta, Yasuhide; Okabe, Susumu; Gotoh, Yukiko

doi:10.1111/gtc.12205

Cited by 13 publications

(16 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cbx3 plays important roles in developmental processes (Morikawa et al 2013). In model systems, Cbx3 promotes neuronal maturation, kidney development, differentiation of ESCs to smooth muscle in culture, and embryonic arteriogenesis (Xiao et al 2011;Dihazi et al 2015;Oshiro et al 2015). Little is known of how Cbx3 functions in differentiation, but its promoter localization suggested that it might directly affect transcription through the preinitiation complex (PIC) (Grunberg and Hahn 2013;Allen and Taatjes 2015).…”

mentioning

confidence: 99%

Cbx3 maintains lineage specificity during neural differentiation

Huang

Xue

et al. 2017

Genes Dev.

View full text Add to dashboard Cite

Chromobox homolog 3 (Cbx3/heterochromatin protein 1γ [HP1γ]) stimulates cell differentiation, but its mechanism is unknown. We found that Cbx3 binds to gene promoters upon differentiation of murine embryonic stem cells (ESCs) to neural progenitor cells (NPCs) and recruits the Mediator subunit Med26. RNAi knockdown of either Cbx3 or Med26 inhibits neural differentiation while up-regulating genes involved in mesodermal lineage decisions. Thus, Cbx3 and Med26 together ensure the fidelity of lineage specification by enhancing the expression of neural genes and down-regulating genes specific to alternative fates.

show abstract

mentioning

confidence: 99%

Cbx3 maintains lineage specificity during neural differentiation

Huang

Xue

et al. 2017

Genes Dev.

View full text Add to dashboard Cite

show abstract

“…Interestingly, a recent study demonstrated that HP1γ protein levels increase in cortical neurons of the mouse embryonic neocortex 11 . Using immunohistochemistry, this study specifically compared the cortical neurons before and after their migration from the ventricular zone.…”

Section: Resultsmentioning

confidence: 99%

“…KLF11), which are involved in the regulation of neuron specific genes, such as the Dopamine receptor D2 10 . Other groups have implicated a role of HP1γ in neuronal differentiation 11 , 12 . However, the mechanism by which HP1γ regulates neuronal cell differentiation and cell functions remains to be established.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying the Regulation of HP1γ by the NGF-PKA Signaling Pathway

Seo¹,

Mathison²,

Grzenda³

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Heterochromatin protein 1 γ (HP1γ) is a well-known chromatin protein, which regulates gene silencing during the execution of processes associated with embryogenesis, organ maturation, and cell differentiation. We find that, in vivo, the levels of HP1γ are downregulated during nervous system development. Similar results are recapitulated in vitro during nerve growth factor (NGF)-induced neuronal cell differentiation in PC12 cells. Mechanistically, our experiments demonstrate that in differentiating PC12 cells, NGF treatment decreases the association of HP1γ to silent heterochromatin, leads to phosphorylation of this protein at S83 via protein kinase A (PKA), and ultimately results in its degradation. Genome-wide experiments, using gain-of-function (overexpression) and loss-of-function (RNAi) paradigms, demonstrate that changing the level of HP1γ impacts on PC12 differentiation, at least in part, through gene networks involved in this process. Hence, inactivation of HP1γ by different post-translational mechanisms, including reduced heterochromatin association, phosphorylation, and degradation, is necessary for neuronal cell differentiation to occur. Indeed, we show that the increase of HP1γ levels has the reverse effect, namely antagonizing neuronal cell differentiation, supporting that this protein acts as a barrier for this process. Thus, these results describe the regulation and participation of HP1γ in a novel membrane-to-nucleus pathway, through NGF-PKA signaling, which is involved in NGF-induced neuronal cell differentiation.

show abstract

“…While multiple molecular pathways including guidance cues and growth factors have been implicated in axonal development 41 , very little is known about chromatin-regulatory mechanisms 43 . Recently, the SET (histone methyltransferase) domain-containing transcriptional repressor, PRDM8, was described as essential for the formation of trans-callosal and other interhemispheric fiber tracts 44 Likewise, heterochromatin-associated protein HP1γ is required for the crossing of callosal axons into the contralateral hemisphere, while increased neuronal HP1γ expression promotes growth and differentiation of dendrites and axons 45 . Interestingly, PRDM8 promotes H3K9 methylation 46 and HP1γ is bound preferentially to compacted nucleosomal arrays bearing the repressive H3K9me3 mark 47 .…”

Section: Discussionmentioning

confidence: 99%

In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene

Peter

Saito²,

Hasegawa

et al. 2018

Preprint

View full text Add to dashboard Cite

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus.C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46 R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons.Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 proteinconjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins. the FOXG1 transcription factor 12 . However, molecular and cellular mechanisms linking the neuronal epigenome to interhemispheric connectivity remain poorly explored.Here, we describe C11orf46/ARL14EP, a small (35kDa) nuclear protein encoded in the chr. 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus, as a novel chromatin regulator of transcallosal connectivity. Importantly, weshow that C11orf46 is, as an RNA-guided Cas9 fusion protein, suitable for targeted epigenomic promoter editing to drive the expression of specific regulators of axonal development in immature transcallosal projection neurons, thereby offering a molecular tool to affect interhemispheric communication. ResultsC11orf46 is expressed in cortical projection neurons and critical for transcallosal connectivity. A recent study identified 50 novel genes associated with autosomal recessive forms of intellectual disability, including open reading frame C11orf46 13 . Importantly, moreover, this gene is located in the chr. 11p13-14 neurodevelopmental risk locus and deleted in some cases of WAGR syndrome (Online Mendelian Inheritance of Man (OMIM) #194072), a rare copy number variant disorder with its core features caused by haploinsufficiency for the Wilms Tumor 1 (...

show abstract

Up‐regulation of HP1γ expression during neuronal maturation promotes axonal and dendritic development in mouse embryonic neocortex

Cited by 13 publications

References 35 publications

Cbx3 maintains lineage specificity during neural differentiation

Cbx3 maintains lineage specificity during neural differentiation

Mechanisms Underlying the Regulation of HP1γ by the NGF-PKA Signaling Pathway

In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene

Contact Info

Product

Resources

About