A SMAD1/5-YAP signaling module drives radial glia self-amplification and growth of the developing cerebral cortex

Najas, Sònia; Pijuan, Isabel; Esteve‐Codina, Anna; Usieto, Susana; Martinez, J.; Zwijsen, An; Arbonés, María L.; Martı́, Elisa; Dréau, Gwenvaël Le

doi:10.1101/558486

Cited by 5 publications

(8 citation statements)

References 64 publications

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“…17 YAP has also been implicated to act downstream of BMP-SMAD1/5 in maintaing production of RGCs and IPCs in the developing cerebral cortex. 38 However, specification of cortical progenitors is preserved and the pattern of neurogenesis is maintained in mice deficient for BMP receptors Bmpr1a and Bmpr1b. 39 Furthermore, deletion of Bmpr1a and Bmpr1b with Emx-Cre only affects the development of dentate gyrus of the hippocampus, but not the cerebral cortex, 40 suggesting that YAP might not regulate cortical progenitors and PNs through the BMP pathway.…”

Section: Discussionmentioning

confidence: 99%

YAP maintains the production of intermediate progenitor cells and upper‐layer projection neurons in the mouse cerebral cortex

Hung

Wang

et al. 2021

Developmental Dynamics

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Background: The Hippo pathway is conserved through evolution and plays critical roles in development, tissue homeostasis and tumorigenesis. Yesassociated protein (YAP) is a transcriptional coactivator downstream of the Hippo pathway. Previous studies have demonstrated that activation of YAP promotes proliferation in the developing brain. Whether YAP is required for the production of neural progenitor cells or neurons in vivo remains unclear. Results: We demonstrated that SATB homeobox 2 (SATB2)-positive projection neurons (PNs) in upper layers, but not T-box brain transcription factor 1-positive and Coup-TF interacting protein 2-positive PNs in deep layers, were decreased in the neonatal cerebral cortex of Yap conditional knockout (cKO) mice driven by Nestin-Cre. Cell proliferation was reduced in the developing cerebral cortex of Yap-cKO. SATB2-positive PNs are largely generated from intermediate progenitor cells (IPCs), which are derived from radial glial cells (RGCs) during cortical development. Among these progenitor cells, IPCs but not RGCs were decreased in Yap-cKO. We further demonstrated that cell cycle re-entry was reduced in progenitor cells of Yap-cKO, suggesting that fewer IPCs were generated in Yap-cKO. Conclusion: YAP is required for the production of IPCs and upper-layer SATB2-positive PNs during development of the cerebral cortex in mice. K E Y W O R D S cerebral cortex, Hippo pathway, intermediate progenitor cells, radial glial cells, YAP | INTRODUCTIONThe Hippo pathway is conserved from Drosophila to mammals and important for organ size control. The core components of the Hippo pathway include mammalian STE20-like protein kinase 1/2 (MST1/2, homologs of Drosophila Hippo), large tumor suppressor 1/2 (LATS1/2; homologs of Drosophila Warts), Salvador family WW domain-containing protein 1 (SAV1; homolog of Drosophila Salvador), MOB kinase activator 1A/B (MOB1A/ B; homologs of Drosophila Mats), Yes-associated protein (YAP; homolog of Drosophila Yorkie), and transcriptional coactivator with PDZ-binding motif (TAZ). 1 MST1/2 are serine/threonine (Ser/Thr) protein kinases, which form a complex with the adaptor protein SAV1 to phosphorylate LATS1/2, two nuclear Dbf2-related (NDR) family Ser/Thr

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Section: Discussionmentioning

confidence: 99%

YAP maintains the production of intermediate progenitor cells and upper‐layer projection neurons in the mouse cerebral cortex

Hung

Wang

et al. 2021

Developmental Dynamics

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“…The distinct increase in mitotic cell behavior outside the VZ areas raises the intriguing question about the underlying mechanisms. Recent data from mice suggest that premature cortical progenitor delamination, ectopic rosette formation, periventricular neuronal heterotopia, and megalencephaly might result from deregulation of the Hippo signaling pathway (Cappello et al , 2013; Liu et al , 2018; O'Neill et al , 2018; Saito et al , 2018; Najas et al , 2020)—a conserved signaling pathway that controls cell proliferation and tissue development (Camargo et al , 2007; Zhao et al , 2011). To assess whether YAP1, a major downstream effector of the Hippo pathway (Sahu & Mondal, 2021), is altered in EML1 ‐deficient cerebral organoids, we investigated YAP1 expression in our scRNAseq data.…”

Section: Resultsmentioning

confidence: 99%

Human cerebral organoids reveal progenitor pathology in EML1‐linked cortical malformation

et al. 2022

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Malformations of human cortical development (MCD) can cause severe disabilities. The lack of human‐specific models hampers our understanding of the molecular underpinnings of the intricate processes leading to MCD. Here, we use cerebral organoids derived from patients and genome edited‐induced pluripotent stem cells to address pathophysiological changes associated with a complex MCD caused by mutations in the echinoderm microtubule‐associated protein‐like 1 (EML1) gene. EML1‐deficient organoids display ectopic neural rosettes at the basal side of the ventricular zone areas and clusters of heterotopic neurons. Single‐cell RNA sequencing shows an upregulation of basal radial glial (RG) markers and human‐specific extracellular matrix components in the ectopic cell population. Gene ontology and molecular analyses suggest that ectopic progenitor cells originate from perturbed apical RG cell behavior and yes‐associated protein 1 (YAP1)‐triggered expansion. Our data highlight a progenitor origin of EML1 mutation‐induced MCD and provide new mechanistic insight into the human disease pathology.

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“…This study revealed a potential role of YAP regulation in NSC proliferation. Similarly, Najas et al showed that BMP-induced Smad1/5 activation could stimulate radial glial cell growth of the developing cerebral cortex, via a direct interaction with YAP and independently of TEAD family transcriptional factors [ 54 ]. However, during the astrocytic differentiation, YAP could stabilize SMAD1 and promote BMP2-induced neocortical astrocytic proliferation and differentiation, revealing a context-dependent role of YAP in NSC amplification and differentiation [ 55 ].…”

Section: Transcriptional Regulations Of Yap/taz In Stem Cell and Differentiationmentioning

confidence: 99%

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation

Luo

2022

Stem Cell Res Ther

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Hippo pathway is initially identified as a master regulator for cell proliferation and organ size control, and the subsequent researches show this pathway is also involved in development, tissue regeneration and homeostasis, inflammation, immunity and cancer. YAP/TAZ, the downstream effectors of Hippo pathway, usually act as coactivators and are dependent on other transcription factors to mediate their transcriptional outputs. In this review, we will first provide an overview on the core components and regulations of Hippo pathway in mammals, and then systematically summarize the identified transcriptional factors or partners that are responsible for the transcriptional output of YAP/TAZ in stem cell and differentiation. More than that, we will discuss the potential applications and future directions based on these findings.

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A SMAD1/5-YAP signaling module drives radial glia self-amplification and growth of the developing cerebral cortex

Abstract: 20 21 Tel: 34-934034972 22 Fax: 34-934034979 23 24One sentence summary: SMAD1/5 control cortical neurogenesis 25 26 27

Cited by 5 publications

References 64 publications

YAP maintains the production of intermediate progenitor cells and upper‐layer projection neurons in the mouse cerebral cortex

YAP maintains the production of intermediate progenitor cells and upper‐layer projection neurons in the mouse cerebral cortex

Human cerebral organoids reveal progenitor pathology in EML1‐linked cortical malformation

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation

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