ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination

Capecchi, Mario R.; Pozner, Amir

doi:10.1038/ncomms9763

Cited by 94 publications

(102 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, Cyclin D2 knockout mice have a thinner cortex; however, not to the massive extent that we observe with Akirin2 knockout mice [45]. Tightly regulated cell cycle progression is clearly essential in early corticogenesis, as microcephaly can also be caused by disruption of centrosomal proteins [46, 47], cell cycle proteins [48] and mitotic sister chromatid cohesion [49], among others. The rapid loss of telencephalic tissue at a very early age (E10-11) complicates the assessment of whether pro-survival and/or proliferation-promoting genes are specifically mis-regulated in Emx1-Cre; Akirin2 fl/fl mutants.…”

Section: Discussionsupporting

confidence: 67%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

View full text Add to dashboard Cite

BackgroundThe proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.MethodsWe generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.ResultsThe vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to “spill” into the lateral ventricle.ConclusionsOur data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0076-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 67%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

View full text Add to dashboard Cite

show abstract

“…4). KO ferrets also showed increased apoptosis in telencephalic germinal zones not seen in Aspm KO mice 5–7,9 (Extended Data Fig. 5), further highlighting that loss of Aspm elicits divergent brain phenotypes in ferrets and mice.…”

Section: Main Textmentioning

confidence: 77%

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

Johnson

Sun

Kodani

et al. 2018

Nature

148

154

View full text Add to dashboard Cite

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding, yet the evolutionary mechanisms driving cortical size and structure are unknown. While genes essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (“small head”, associated with reduced brain size and intellectual disability)1, studies of these genes in mice, whose smooth cortex is one thousand times smaller than that of humans, have provided limited insight. Mutations of abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by ≥50% in humans2–4, but have little effect in mice5–9, likely reflecting evolutionarily divergent functions of ASPM10,11. We used genome editing to create a germline knockout (KO) of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell (NPC) diversity12–14 than mice, and closer Aspm protein sequence homology to human. Aspm KO ferrets exhibit severe microcephaly (25–40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as in human patients3,4, suggesting loss of “cortical units”. The mutant ferret fetal cortex displays a massive premature displacement of ventricular radial glial cells (VRG) to the outer subventricular zone (OSVZ), where many resemble outer radial glia (ORG), an NPC subtype essentially absent in mice and implicated in cerebral cortical expansion in primates12–16. These data suggest an evolutionary mechanism whereby Aspm regulates cortical expansion by controlling the affinity of VRG for the ventricular surface, thus modulating the ratio of VRG, the most undifferentiated cell type, to ORG, a more differentiated progenitor.

show abstract

“…ASPM is a conserved protein that associates with the MT minus ends, is recruited at the spindle poles during mitosis, and controls spindle MT organization, spindle function, and cytokinesis from insects to mammals [39][40][41]. Recent evidence indicates that ASPM may control cell fate choice by regulating the activity of Cdk2/cyclin E complex [43]. Recent evidence indicates that ASPM may control cell fate choice by regulating the activity of Cdk2/cyclin E complex [43].…”

Section: Introductionmentioning

confidence: 99%

“…In mammals, NE cells with reduced ASPM expression fail to orient the mitotic spindle perpendicular to the ventricular surface of the neuroepithelium and show increased frequency of asymmetric divisions, with a reduction of the pool of neuronal precursors [25,42]. Recent evidence indicates that ASPM may control cell fate choice by regulating the activity of Cdk2/cyclin E complex [43]. However, it is presently unknown how ASPM regulates spindle orientation.…”

Section: Introductionmentioning

confidence: 99%

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

et al. 2016

View full text Add to dashboard Cite

Correct orientation of cell division is considered an important factor for the achievement of normal brain size, as mutations in genes that affect this process are among the leading causes of microcephaly. Abnormal spindle orientation is associated with reduction of the neuronal progenitor symmetric divisions, premature cell cycle exit, and reduced neurogenesis. This mechanism has been involved in microcephaly resulting from mutation of ASPM, the most frequently affected gene in autosomal recessive human primary microcephaly (MCPH), but it is presently unknown how ASPM regulates spindle orientation. In this report, we show that ASPM may control spindle positioning by interacting with citron kinase (CITK), a protein whose loss is also responsible for severe microcephaly in mammals. We show that the absence of CITK leads to abnormal spindle orientation in mammals and insects. In mouse cortical development, this phenotype correlates with increased production of basal progenitors. ASPM is required to recruit CITK at the spindle, and CITK overexpression rescues ASPM phenotype. ASPM and CITK affect the organization of astral microtubules (MT), and low doses of MT-stabilizing drug revert the spindle orientation phenotype produced by their knockdown. Finally, CITK regulates both astral-MT nucleation and stability. Our results provide a functional link between two established microcephaly proteins.

show abstract

ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination

Cited by 94 publications

References 69 publications

Akirin2 is essential for the formation of the cerebral cortex

Akirin2 is essential for the formation of the cerebral cortex

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

Contact Info

Product

Resources

About