Notch3 signaling gates cell cycle entry and limits neural stem cell amplification in the adult pallium

Development (Impact Factor: 6.46). 07/2013; 140(16). DOI: 10.1242/dev.095018
Source: PubMed


Maintaining the homeostasis of germinal zones in adult organs is a fundamental but mechanistically poorly understood process. In particular, what controls stem cell activation remains unclear. We have previously shown that Notch signaling limits neural stem cell (NSC) proliferation in the adult zebrafish pallium. Combining pharmacological and genetic manipulations, we demonstrate here that long-term Notch invalidation primarily induces NSC amplification through their activation from quiescence and increased occurrence of symmetric divisions. Expression analyses, morpholino-mediated invalidation and the generation of a notch3-null mutant directly implicate Notch3 in these effects. By contrast, abrogation of notch1b function results in the generation of neurons at the expense of the activated NSC state. Together, our results support a differential involvement of Notch receptors along the successive steps of NSC recruitment. They implicate Notch3 at the top of this hierarchy to gate NSC activation and amplification, protecting the homeostasis of adult NSC reservoirs under physiological conditions.

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    • "The heterogeneous expression patterns of notch receptors and ligands suggest that different combinations may regulate progenitor proliferation or cell fate determination (Alunni et al., 2013; Okigawa et al., 2014). To determine in which cells Notch signaling is active, we analyzed the expression pattern of the Notch reporter Tg(Tp1bglob:eEGFP) crossed with Tg(atoh1a: dTomato) that labels hair cells. "
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    ABSTRACT: In vertebrates, mechano-electrical transduction of sound is accomplished by sensory hair cells. Whereas mammalian hair cells are not replaced when lost, in fish they constantly renew and regenerate after injury. In vivo tracking and cell fate analyses of all dividing cells during lateral line hair cell regeneration revealed that support and hair cell progenitors localize to distinct tissue compartments. Importantly, we find that the balance between self-renewal and differentiation in these compartments is controlled by spatially restricted Notch signaling and its inhibition of Wnt-induced proliferation. The ability to simultaneously study and manipulate individual cell behaviors and multiple pathways in vivo transforms the lateral line into a powerful paradigm to mechanistically dissect sensory organ regeneration. The striking similarities to other vertebrate stem cell compartments uniquely place zebrafish to help elucidate why mammals possess such low capacity to regenerate hair cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 07/2015; 34(3). DOI:10.1016/j.devcel.2015.05.025 · 9.71 Impact Factor
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    • "Whole-mount ISH were performed as previously described (Parmentier et al., 2011; Alunni et al., 2013) on embryos or dissected adult spinal cords fixed in 4% PFA in PBS overnight at 4 • C. "
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    ABSTRACT: Over 90 years ago, Kolmer and Agduhr identified spinal cerebrospinal fluid-contacting neurons (CSF-cNs) based on their morphology and location within the spinal cord. In more than 200 vertebrate species, they observed ciliated neurons around the central canal that extended a brush of microvilli into the cerebrospinal fluid (CSF). Although their morphology is suggestive of a primitive sensory cell, their function within the vertebrate spinal cord remains unknown. The identification of specific molecular markers for these neurons in vertebrates would benefit the investigation of their physiological roles. PKD2L1, a transient receptor potential channel that could play a role as a sensory receptor, has been found in cells contacting the central canal in mouse. In this study, we demonstrate that PKD2L1 is a specific marker for CSF-cNs in the spinal cord of mouse (Mus musculus), macaque (Macaca fascicularis) and zebrafish (Danio rerio). In these species, the somata of spinal PKD2L1(+) CSF-cNs were located below or within the ependymal layer and extended an apical bulbous extension into the central canal. We found GABAergic PKD2L1-expressing CSF-cNs in all three species. We took advantage of the zebrafish embryo for its transparency and rapid development to identify the progenitor domains from which pkd2l1 (+) CSF-cNs originate. pkd2l1 (+) CSF-cNs were all GABAergic and organized in two rows-one ventral and one dorsal to the central canal. Their location and marker expression is consistent with previously described Kolmer-Agduhr cells. Accordingly, pkd2l1 (+) CSF-cNs were derived from the progenitor domains p3 and pMN defined by the expression of nkx2.2a and olig2 transcription factors, respectively. Altogether our results suggest that a system of CSF-cNs expressing the PKD2L1 channel is conserved in the spinal cord across bony vertebrate species.
    Frontiers in Neuroanatomy 05/2014; 8:26. DOI:10.3389/fnana.2014.00026 · 3.54 Impact Factor
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    • "This suggests that other members of the Notch family could provide a maintenance signal for quiescent NSCs and compensate for the absence of Notch1 in this population (Basak et al., 2012). Heterogeneity of Notch activity is related to cellular diversity in the neurogenic niches of the adult zebrafish brain, where Notch3 gates NSC activation whereas Notch1b maintains activated progenitors (Alunni et al., 2013). Interestingly, Notch3 restricts stem cell activation in muscle and mammary, while Notch1 is associated with proliferation (Carlson et al., 2008; Kitamoto and Hanaoka, 2010; Bjornson et al., 2012; Mourikis et al., 2012; Lafkas et al., 2013). "
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    ABSTRACT: Adult neural stem cells (NSCs) are perceived as a homogeneous population of cells that divide infrequently and are capable of multi-lineage differentiation. However, recent data revealed that independent stem cell lineages act in parallel to maintain neurogenesis and provide a cellular source for tissue repair. In addition, even within the same lineage, the stem and progenitor cells are strikingly heterogeneous including NSCs that are dormant or mitotically active. We will discuss these different NSC populations and activity states with relation to their role in neurogenesis and regeneration but also how these different stem cells respond to aging. NSCs depend on Notch signaling for their maintenance. While Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to adult NSC heterogeneity. Understanding the fate of multiple NSC populations with distinct functions has implications for the mechanisms of aging and regeneration.
    Frontiers in Neuroscience 02/2014; 8(8):32. DOI:10.3389/fnins.2014.00032 · 3.66 Impact Factor
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