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1.
Dev Biol ; 457(1): 150-162, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31586559

ABSTRACT

Yap/Taz are well-established downstream effectors of the Hippo pathway, known to regulate organ size by directing proliferation and apoptosis. Although the functions of Yap/Taz have been extensively studied, little is known about their role in brain development. Here, through genetic ablation, we show that Yap/Taz are required for cerebellar morphogenesis. Yap/Taz deletion in neural progenitors causes defects in secondary fissure formation, leading to abnormal folia development. Although they seemed very likely to serve an important function in the development of cerebellar granule cell precursors, Yap/Taz are dispensable for their proliferation. Furthermore, Yap/Taz loss does not rescue the medulloblastoma phenotype caused by constitutively active Smoothened. Importantly, Yap/Taz are highly expressed in radial glia and play a crucial role in establishing the radial scaffold and cellular polarity of neural progenitors during embryogenesis. We found that Yap/Taz are necessary to establish and maintain junctional integrity of cerebellar neuroepithelium as prominent junction proteins are not maintained at the apical junction in the absence of Yap/Taz. Our study identifies a novel function of Yap/Taz in cerebellar foliation and finds that they are required to establish the radial glia scaffold and junctional stability.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Cycle Proteins/metabolism , Cerebellum/embryology , Organogenesis , Trans-Activators/metabolism , Animals , Cell Proliferation , Cerebellum/cytology , Cerebellum/metabolism , Ependymoglial Cells , Mice , Organ Size , Stem Cells/metabolism , YAP-Signaling Proteins
2.
Nat Commun ; 7: 10329, 2016 Jan 12.
Article in English | MEDLINE | ID: mdl-26754915

ABSTRACT

Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells. Importantly, an injury signal initiated by lysophosphatidic acid (LPA), an upstream regulator of Yap that can cause fetal haemorrhagic hydrocephalus, deregulates Yap in the developing aqueduct. LPA exposure leads to the loss of N-cadherin concentrations at the apical endfeet, which can be partially restored by forced Yap expression and more efficiently by phosphomimetic Yap. These results reveal a novel function of Yap in retaining tissue junctions during normal development and after fetal brain injury.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cerebral Aqueduct/metabolism , Ependyma/metabolism , Gene Expression Regulation, Developmental , Hydrocephalus/metabolism , Phosphoproteins/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Blotting, Western , Brain/metabolism , Brain/pathology , Cadherins/metabolism , Cell Cycle Proteins , Cerebral Aqueduct/pathology , Ependyma/pathology , Fetal Diseases , Hydrocephalus/chemically induced , Hydrocephalus/pathology , Immunohistochemistry , Lysophospholipids/toxicity , Mice , Phosphoproteins/metabolism , YAP-Signaling Proteins
3.
Development ; 143(1): 133-46, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26657772

ABSTRACT

Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals and cell types make the cerebellum an excellent model for addressing the crucial function of polarity complex proteins in the generation and organization of neural tissues. Deletion of the apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors in the external granule layer. In the Pals1 mouse mutants, the expression of genes that regulate the cell cycle was diminished, correlating with the loss of the proliferating cell population of germinal zones. Furthermore, enhanced Shh signaling through activated Smo cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a novel intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling.


Subject(s)
Cell Proliferation/genetics , Cerebellum/embryology , Membrane Proteins/metabolism , Neurogenesis/physiology , Nucleoside-Phosphate Kinase/metabolism , Stem Cells/cytology , Animals , Cell Cycle/genetics , Cerebellum/cytology , Gene Expression Regulation, Developmental , Hedgehog Proteins/metabolism , Membrane Proteins/genetics , Mice , Mice, Knockout , Neuroglia/cytology , Nucleoside-Phosphate Kinase/genetics , Organogenesis/genetics , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/genetics , Smoothened Receptor
4.
Cell Rep ; 12(6): 965-78, 2015 Aug 11.
Article in English | MEDLINE | ID: mdl-26235615

ABSTRACT

Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Extracellular Matrix Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/metabolism , Serine Endopeptidases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Adhesion Molecules, Neuronal/genetics , Cell Movement/genetics , Cell Movement/physiology , Cullin Proteins/genetics , Cullin Proteins/metabolism , Extracellular Matrix Proteins/genetics , Female , Humans , Immunohistochemistry , Immunoprecipitation , Male , Mechanistic Target of Rapamycin Complex 1 , Mice , Models, Biological , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Mutation , Nerve Tissue Proteins/genetics , Neurogenesis/genetics , Neurogenesis/physiology , Reelin Protein , Reverse Transcriptase Polymerase Chain Reaction , Serine Endopeptidases/genetics , Signal Transduction/genetics , Signal Transduction/physiology , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
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