Microcephaly as a cell cycle disease

Doobin, David J.; Dantas, Tiago J.; Vallee, Richard B.

doi:10.1080/15384101.2016.1252591

Cited by 11 publications

(11 citation statements)

References 7 publications

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“…Further, defects in microtubule dynamics can lead to lissencephaly and microcephaly two common neurodevelopmental defects due to improper growth of the brain. This prompted some to suggest that impaired INM, a microtubule-dependent phenomenon, might contribute to these pathologies [49,50]. However, all of these microtubule-related defects have also problems in neuronal migration, mitotic spindle positioning and proliferation making it difficult to identify the effects specifically due to a lack of INM.…”

Section: Discussionmentioning

confidence: 99%

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation

et al. 2019

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Pseudostratified epithelia (PSE) are a common type of columnar epithelia found in a wealth of embryonic and adult tissues such as ectodermal placodes, the trachea, the ureter, the gut and the neuroepithelium. PSE are characterized by the choreographed displacement of cells' nuclei along the apicobasal axis according to phases of their cell cycle. Such movements, called interkinetic movements (INM), have been proposed to influence tissue expansion and shape and suggested as culprit in several congenital diseases such as CAKUT (Congenital anomalies of kidney and urinary tract) and esophageal atresia. INM rely on cytoskeleton dynamics just as adhesion, contractility and mitosis do. Therefore, long term impairment of INM without affecting proliferation and adhesion is currently technically unachievable. Here we bypassed this hurdle by generating a 2D agent-based model of a proliferating PSE and compared its output to the growth of the chick neuroepithelium to assess the interplay between INM and these other important cell processes during growth of a PSE. We found that INM directly generates apical expansion and apical nuclear crowding. In addition, our data strongly suggest that apicobasal elongation of cells is not an emerging property of a proliferative PSE but rather requires a specific elongation program. We then discuss how such program might functionally link INM, tissue growth and differentiation. Author summaryPseudostratified epithelia (PSE) are a common type of epithelia characterized by the choreographed displacement of cells' nuclei along the apicobasal axis during proliferation. These so-called interkinetic movements (INM) were proposed to influence tissue expansion and suggested as culprit in several congenital diseases. INM rely on cytoskeleton dynamics. Therefore, longer term impairment of INM without affecting proliferation and adhesion is currently technically unachievable. We bypassed this hurdle by generating a mathematical model of PSE and compared it to the growth of an epithelium of reference.Our data show that INM drive expansion of the apical domain of the epithelium and suggest that apicobasal elongation of cells is not an emerging property of a proliferative PSE but might rather requires a specific elongation program.Interkinetic movements impact the growth of pseudostratified epithelia PLOS Computational Biology | https://doi.

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Section: Discussionmentioning

confidence: 99%

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation

et al. 2019

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“…Primary, i.e., congenital microcephaly, is a genetically heterogeneous disorder often caused by variants in genes coding for proteins regulating cell cycle, e.g., centrosome assembly and duplication or mitotic spindle formation and orientation. [19][20][21][22][23] Many microcephaly subjects present with simplified gyration of the cerebral cortex, without overt structural anomalies, non-progressive intellectual disability, and normal life expectancy. However, another group of children presenting with congenital microcephaly is characterized by severe and progressive encephalopathy and early demise.…”

Section: Smpd4-related Phenotypesmentioning

confidence: 99%

“…Variants in several genes encoding key players of the mitotic process have been described in subjects with congenital microcephaly, implicating cell cycle alterations in the pathogenesis of this disorder. 19,20 Sphingolipids are also implicated in cell cycle regulation and SMPD4 knockdown in HeLa cells causes defects in actin cytoskeleton leading to metaphase delay during mitosis, aberrant cytokinesis and cell division failure. 17 In the present study, cell cycle investigations indicated mitotic defects and susceptibility to apoptosis in native SMPD4-deficient cells and analysis of biological and molecular functions of DEGs in fibroblasts from affected individuals revealed enrichment for genes involved in cellular growth, supporting a role of SMPD4 in cell cycle regulation.…”

Section: Smpd4 Cellular Localization and Cell Cycle Investigationmentioning

confidence: 99%

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Magini

Smits

Vandervore

et al. 2019

The American Journal of Human Genetics

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Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

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“…The overlap between NDE1 and STIL could be explained by the interaction of both genes on primary cilia regulation/signaling and certeriole function. (Doobin, Dantas, & Vallee, 2017).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic spectrum of NDE1‐related disorders: from microlissencephaly to microhydranencephaly

Abdel‐Hamid

El-Dessouky

Ateya

et al. 2019

American J of Med Genetics Pt A

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Biallelic variants in the NDE1 gene have been shown to occur in extreme microcephaly. Most of the patients displayed microlissencephaly but one with microhydranencephaly. We report on three sibs in which the brain MRI and CT scans demonstrated variable degree of reduced volume of cerebral hemispheres and ventriculomegaly. Further, they had agenesis of corpus callosum, cerebellar, and brainstem hypoplasia. Fetal ultrasound at 32 weeks' gestation of the third sib revealed severe micrencephaly with extensive hydranencephaly and an anomaly consistent with non cleaved (fused) thalami. Because of the fused thalami, the STIL gene was targeted initially but showed negative results. His postnatal MRI showed that the cerebral hemispheres are markedly reduced in size (with no definite frontal, parietal, or occipital lobes) and replaced by a large sac filled with CSF. An intact falx cerebri was identified. This extensive hydarencephaly led us to consider the NDE1 and to identify a novel homozygous nonsense variant (c.54G>A, p.W18*). The variability of the degree of brain malformations and the apparent fusion of the thalami were illusive and delayed the recognition of the genetic etiology. Our results provide the first antenatal description of this rare syndrome. Further, we expand the genetic architecture and the neuroradiologic phenotype of NDE1-related disorders.

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Microcephaly as a cell cycle disease

Cited by 11 publications

References 7 publications

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Phenotypic spectrum of NDE1‐related disorders: from microlissencephaly to microhydranencephaly

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