EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation

Abdi, Khadar; Neves, Gabriel Pereira das; Pyun, Joon; Kiziltug, Emre; Ahrens, Angelica P.; Kuo, Chay T.

doi:10.1016/j.celrep.2019.07.056

Cited by 17 publications

(20 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We then established cultures of NPCs derived from the lateral ventricular wall at P0 according to a previously described protocol for the study of ependymal differentiation 56 . These NPCs were cultured first in the presence of 10% fetal bovine serum (FBS) and subsequently in the absence of serum, with serum removal inducing differentiation of the NPCs into multiciliated ependymal cells 46 , 56 . We found that the amount of Id1 protein, as well as that of Id4 protein to a lesser extent, in the cultured cells was reduced in response to serum removal, and that this effect appeared to coincide with the initial induction of Foxj1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the context of embryonic NPCs in the SVZ, whereas overexpression of Geminin increases the number of clones that contain adult NSCs, that of GemC1 increases the number of those containing muticiliated ependymal cells, supporting the notion that GemC1 plays a key role in the early fate specification of ependymal cells 28 . Whereas Notch signaling, epidermal growth factor receptor (EGFR) signaling, and the extracellular matrix (ECM) protein dystroglycan have been shown to regulate the expression of Mcidas and Foxj1 during ependymal maturation 31 , 46 – 48 , little is known of the extracellular signals that may regulate the expression of GemC1 and thereby contribute to the specification and differentiation of ependymal cells during embryonic and early-postnatal telencephalic development.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

Omiya

Yamaguchi

Watanabe

et al. 2021

Sci Rep

View full text Add to dashboard Cite

The lateral ventricles of the adult mammalian brain are lined by a single layer of multiciliated ependymal cells, which generate a flow of cerebrospinal fluid through directional beating of their cilia as well as regulate neurogenesis through interaction with adult neural stem cells. Ependymal cells are derived from a subset of embryonic neural stem-progenitor cells (NPCs, also known as radial glial cells) that becomes postmitotic during the late embryonic stage of development. Members of the Geminin family of transcriptional regulators including GemC1 and Mcidas play key roles in the differentiation of ependymal cells, but it remains largely unclear what extracellular signals regulate these factors and ependymal differentiation during embryonic and early-postnatal development. We now show that the levels of Smad1/5/8 phosphorylation and Id1/4 protein expression—both of which are downstream events of bone morphogenetic protein (BMP) signaling—decline in cells of the ventricular-subventricular zone in the mouse lateral ganglionic eminence in association with ependymal differentiation. Exposure of postnatal NPC cultures to BMP ligands or to a BMP receptor inhibitor suppressed and promoted the emergence of multiciliated ependymal cells, respectively. Moreover, treatment of embryonic NPC cultures with BMP ligands reduced the expression level of the ependymal marker Foxj1 and suppressed the emergence of ependymal-like cells. Finally, BMP ligands reduced the expression levels of Gemc1 and Mcidas in postnatal NPC cultures, whereas the BMP receptor inhibitor increased them. Our results thus implicate BMP signaling in suppression of ependymal differentiation from NPCs through regulation of Gemc1 and Mcidas expression during embryonic and early-postnatal stages of mouse telencephalic development.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

Omiya

Yamaguchi

Watanabe

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Adult ependymal cells coexist primarily as E1 multiciliate cells (approximately 50 cilia per cell) and E2 biciliated cells (less than 5% total), lining the walls of the lateral ventricles, the third dorsal ventricle, and the fourth ventricle to create a cerebrospinal fluid (CSF) flow constant 1 . Both cell types constitute highly polarized cells generated from radial glial cells 2 – 4 , that protect the brain parenchyma from direct contact with CSF, among other functions 5 , 6 . The stability of this epithelium is maintained by the presence of functional adherens junctions 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

IIIG9 inhibition in adult ependymal cells changes adherens junctions structure and induces cellular detachment

Baeza

Cifuentes

Martínez

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Ependymal cells have multiple apical cilia that line the ventricular surfaces and the central canal of spinal cord. In cancer, the loss of ependymal cell polarity promotes the formation of different types of tumors, such as supratentorial anaplastic ependymomas, which are highly aggressive in children. IIIG9 (PPP1R32) is a protein restricted to adult ependymal cells located in cilia and in the apical cytoplasm and has unknown function. In this work, we studied the expression and localization of IIIG9 in the adherens junctions (cadherin/β-catenin-positive junctions) of adult brain ependymal cells using confocal and transmission electron microscopy. Through in vivo loss-of-function studies, ependymal denudation (single-dose injection experiments of inhibitory adenovirus) was observed, inducing the formation of ependymal cells with a “balloon-like” morphology. These cells had reduced cadherin expression (and/or delocalization) and cleavage of the cell death marker caspase-3, with “cilia rigidity” morphology (probably vibrational beating activity) and ventriculomegaly occurring prior to these events. Finally, after performing continuous infusions of adenovirus for 14 days, we observed total cell denudation and reactive parenchymal astrogliosis. Our data confirmed that IIIG9 is essential for the maintenance of adherens junctions of polarized ependymal cells. Eventually, altered levels of this protein in ependymal cell differentiation may increase ventricular pathologies, such as hydrocephalus or neoplastic transformation.

show abstract

“…To validate its ciliary localization, we expressed V5 tagged Numb in NIH3T3 cells. We found that in addition to its reported distribution in the cytosol as puncta (Abdi et al, 2019; Nishimura and Kaibuchi, 2007), Numb-V5 also overlaps with the ciliary marker Arl13b. However, the Numb immunofluorescence signal is not distributed along the entire cilium; rather, it is restricted to the lower four-fifths of the cilium (Fig.…”

Section: Resultsmentioning

confidence: 66%

Cilium proteomics reveals Numb as a positive regulator of the Hedgehog signaling pathway

Liu

Yam

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

The transduction of Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle acting as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identified Numb as a new ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impaired Sonic Hedgehog-induced Ptch1 departure from the cilium, resulting in severe attenuation of Hh signaling. Genetic ablation of Numb and its homolog Numblike in the developing cerebellum impaired the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study demonstrates a key function of Numb in controlling protein levels in the cilium, and highlights Numb's critical role in the regulation of Hh signaling.

show abstract

EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation

Cited by 17 publications

References 55 publications

BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

BMP signaling suppresses Gemc1 expression and ependymal differentiation of mouse telencephalic progenitors

IIIG9 inhibition in adult ependymal cells changes adherens junctions structure and induces cellular detachment

Cilium proteomics reveals Numb as a positive regulator of the Hedgehog signaling pathway

Contact Info

Product

Resources

About