Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Fiddes, Ian T.; Lodewijk, Gerrald A.; Mooring, Meghan; Bosworth, Colleen M.; Ewing, Adam D.; Mantalas, Gary L.; Novak, Adam M.; Bout, Anouk van den; Bishara, Alex; Rosenkrantz, Jimi L.; Lorig-Roach, Ryan; Field, Andrew R.; Haeussler, Maximilian; Russo, Lotte; Bhaduri, Aparna; Nowakowski, Tomasz J.; Pollen, Alex A.; Dougherty, Max L.; Nuttle, Xander; Addor, Marie‐Claude; Zwolinski, Simon; Katzman, Sol; Kriegstein, Arnold R.; Eichler, Evan E.; Salama, Sofie R.; Jacobs, Frank M. J.; Haussler, David

doi:10.1016/j.cell.2018.03.051

Cited by 396 publications

(367 citation statements)

References 56 publications

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“…This is particularly evident in the case of the brain, where the expansion of the human forebrain is one of the most prominent and rapid evolutionary changes among mammals. The evolutionary genetic changes involved in the expansion of the forebrain encompass two main mechanisms: the generation of novel genes through gene duplication (Fiddes et al, 2018;Suzuki et al, 2018;Charrier et al, 2012;Florio et al, 2015), and differential gene regulation at the transcriptional (i.e., enhancers) (Boyd et al, 2015) and post-transcriptional (i.e., lnc-RNAs) (Pollard et al, 2006) levels. In this study, we present new evidences about the functional role of human-specific substitutions in an active ultraconserved enhancer controlling Foxg1 expression during early neural development stages and their consequences on human forebrain evolution.…”

Section: Discussionmentioning

confidence: 99%

A Human Accelerated Region participates in early human forebrain patterning and expansion

Acosta

Sidhaye

Fiore³

et al. 2019

Preprint

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The expansion of the mammalian brain is associated with specific developmental processes; however, not much is known about how evolutionary changes participated in the acquisition of human brain traits during early developmental stages. Here we investigated whether enhancers active during the phylotypic stage show human-specific genomic divergence which could contribute to the evolutionary expansion of the forebrain. Notably, we identified an active enhancer containing a human accelerated region (HAR) located in the Chromosome 14q12, a region enriched with neurodevelopmental genes, such as Foxg1, Nkx2.1 and Nova1. Reporter analysis revealed that the human variant is active in the forebrain in transgenic mice and that it has stronger enhancer activity than the mouse or chimpanzee versions. Humanization of the mouse enhancer variant in transgenic mice and in mouse organoids resulted in an expansion of Foxg1 expressing domains in the forebrain early neural progenitors with a bias towards dorsal identities. Overall, our results suggest that human-specific mutations in critical regulatory elements controlling early brain development impact the expansion and patterning of the forebrain.

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Section: Discussionmentioning

confidence: 99%

A Human Accelerated Region participates in early human forebrain patterning and expansion

Acosta

Sidhaye

Fiore³

et al. 2019

Preprint

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“…46 Note that overexpression of NOTCH2NL and gain of DUF1220 are associated with an increased brain size, both developmentally within the human and evolutionarily within the primate population. 47 …”

Section: Astrocytoma Tumor-exclusive Genotype and Phenotypementioning

confidence: 99%

Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype

2018

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DNA alterations have been observed in astrocytoma for decades. A copy-number genotype predictive of a survival phenotype was only discovered by using the generalized singular value decomposition (GSVD) formulated as a comparative spectral decomposition. Here, we use the GSVD to compare whole-genome sequencing (WGS) profiles of patient-matched astrocytoma and normal DNA. First, the GSVD uncovers a genome-wide pattern of copy-number alterations, which is bounded by patterns recently uncovered by the GSVDs of microarray-profiled patient-matched glioblastoma (GBM) and, separately, lower-grade astrocytoma and normal genomes. Like the microarray patterns, the WGS pattern is correlated with an approximately one-year median survival time. By filling in gaps in the microarray patterns, the WGS pattern reveals that this biologically consistent genotype encodes for transformation via the Notch together with the Ras and Shh pathways. Second, like the GSVDs of the microarray profiles, the GSVD of the WGS profiles separates the tumor-exclusive pattern from normal copy-number variations and experimental inconsistencies. These include the WGS technology-specific effects of guaninecytosine content variations across the genomes that are correlated with experimental batches. Third, by identifying the biologically consistent phenotype among the WGS-profiled tumors, the GBM pattern proves to be a technology-independent predictor of survival and response to chemotherapy and radiation, statistically better than the patient’s age and tumor’s grade, the best other indicators, and MGMT promoter methylation and IDH1 mutation. We conclude that by using the complex structure of the data, comparative spectral decompositions underlie a mathematically universal description of the genotype-phenotype relations in cancer that other methods miss.

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“…Recent visualization of the structures of Notch-decorating glycosyltransferases and the frosted Notch receptors in complex with Notch ligands has advanced our understanding of the significance of glycosylation in Notch regulation (Kovall, Gebelein, Sprinzak, & Kopan, 2017;Li et al, 2017;Luca et al, 2015Luca et al, , 2017Taylor et al, 2014;Yu et al, 2016Yu et al, , 2015. Recently, two groups independently identified the human-specific paralogs of NOTCH2, called NOTCH2NL, that only encode the region corresponding to the first six EGF repeats of NOTCH2, and are involved in the expansion of cortical neurogenesis in human brains through the activation of Notch signaling (Fiddes et al, 2018;Suzuki et al, 2018). Recently, two groups independently identified the human-specific paralogs of NOTCH2, called NOTCH2NL, that only encode the region corresponding to the first six EGF repeats of NOTCH2, and are involved in the expansion of cortical neurogenesis in human brains through the activation of Notch signaling (Fiddes et al, 2018;Suzuki et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Effects of Notch glycosylation on health and diseases

Urata

Takeuchi

2019

Dev Growth Differ

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Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell-fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch-modifying glycosyltransferase. Since then, glycosylation-a post-translational modification involving literal sugars-on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse Oglycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor-like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation. K E Y W O R D S

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Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis

Cited by 396 publications

References 56 publications

A Human Accelerated Region participates in early human forebrain patterning and expansion

A Human Accelerated Region participates in early human forebrain patterning and expansion

Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype

Effects of Notch glycosylation on health and diseases

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