The Orphan Nuclear Receptor TLX Represses Hes1 Expression, Thereby Affecting NOTCH Signaling and Lineage Progression in the Adult SEZ

Luque-Molina, Inma; Shi, Yan; Abdullah, Yomn; Hölzl‐Wenig, Gabriele; Mandl, Claudia; Ciccolini, Francesca

doi:10.1016/j.stemcr.2019.05.004

Cited by 10 publications

(25 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine in what subclusters Lrig1 expression is the highest, we calculated the mean expression level within each subcluster. To verify the accuracy of the result, several well-known marker genes were also analyzed: Nr2e1 [40,41], Ascl1 [42], and Dcx. As expected, this analysis revealed that Nr2e1 and Ascl1 expression levels peaked in activated stem cells, and Dcx expression level peaked in neuroblasts ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life

Nam

Capecchi

2020

Neural Dev

View full text Add to dashboard Cite

Background: Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) regulates stem cell quiescence. As a marker, it identifies stem cells in multiple organs of the mouse. We had detected Lrig1 expression in cultured Id1 high neural stem cells obtained from the lateral walls lining the lateral ventricles of the adult mouse brain. Thus, we investigated whether Lrig1 expression also identifies stem cells in that region in vivo. Methods: Publicly available single cell RNA sequencing datasets were analyzed with Seurat and Monocle. The Lrig1+ cells were lineage traced in vivo with a novel non-disruptive co-translational Lrig1 T2A-iCreERT2 reporter mouse line. Results: Analysis of single cell RNA sequencing datasets suggested Lrig1 was highly expressed in the most primitive stem cells of the neurogenic lineage in the lateral wall of the adult mouse brain. In support of their neurogenic stem cell identity, cell cycle entry was only observed in two morphologically distinguishable Lrig1+ cells that could also be induced into activation by Ara-C infusion. The Lrig1+ neurogenic stem cells were observed throughout the lateral wall. Neuroblasts and neurons were lineage traced from Lrig1+ neurogenic stem cells at 1 year after labeling. Conclusions: We identified Lrig1 as a marker of long-term neurogenic stem cells in the lateral wall of the mouse brain. Lrig1 expression revealed two morphotypes of the Lrig1+ cells that function as long-term neurogenic stem cells. The spatial distribution of the Lrig1+ neurogenic stem cells suggested all subtypes of the adult neurogenic stem cells were labeled.

show abstract

Section: Resultsmentioning

confidence: 99%

Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life

Nam

Capecchi

2020

Neural Dev

View full text Add to dashboard Cite

show abstract

“…The difference in proliferation pattern between the two genotypes may reflect the greater role that Tlx plays in activated apical NSCs and TAPs, where the orphan nuclear receptor was found to be particularly highly expressed. Likewise, activated apical NSCs and TAPs, which are absent in Tlx -/mice, may be necessary to transmit Notch signaling across the apical/basal axis of the niche and this can be the explanation of the different results obtained from WT and Tlx -/mouse model studied before (Luque-Molina et al 2019) . However, we cannot exclude the possibility that Hes1 expression, which in the absence of Tlx is also increased in basal progenitors, prevents the downregulation of Notch activation in this population.…”

Section: Discussionmentioning

confidence: 99%

“…Wildtype and hGFAP-tTA;H2B-GFP (hGFAP;H2B-GFP) mice were sacrificed by CO2 inhalation followed by cervical dislocation (adult), or by decapitation (neonatal). For DiI analyses, brains were placed on a petri dish, the V-SVZ apical surface was exposed and DiI (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine Perchlorate, ThermoFisher Scientific) was applied for 1 minute followed by washing in sort medium (Luque-Molina et al 2019). The V-SVZ was dissected and clonal analysis was performed as previously described (Ciccolini et al 2005).…”

Section: Animals and Svz Dissectionmentioning

confidence: 99%

“…Since the Tlx-Hes1 axis appears to play a role in the activation of apical NSCs, we next downregulated Hes1 expression in specifically apical NSCs to determine the effect on Notch activation and proliferation dynamics in apical and basal NSCs. To specifically downregulate Hes1 expression in the apical V-SVZ, we took advantage of intraventricular injection of adeno associated virus (AAV) constitutively expressing GFP and either a Hes1 specific short hairpin (AAV-Hes1-sh) or a scramble control (AAV-sc-sh) as described before (Luque-Molina et al 2019). With this approach, beside apical NSCs, we also target ependymal cells, which also express Hes-1 (Stratton et al 2019).…”

Section: Regulators Of Nsc Activation Are Differentially Expressed Inmentioning

confidence: 99%

See 1 more Smart Citation

A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

Baur

Abdullah

Mandl

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ) contribute to olfaction by being the origin of most adult-born olfactory bulb (OB) interneurons. The current consensus maintains that adult NSCs are radial glialike progenitors apically contacting the lateral ventricle and generating intermediate progenitors migrating at the basal V-SVZ. Whether basal NSCs are present in the V-SVZ is unknown. We here used genetic tagging of NSCs in vivo and additional labelling approaches to reveal that basal NSCs lacking apical attachment represent the largest NSC type in the postnatal V-SVZ from birth onwards. Despite dividing faster than their apical counterpart, basal NSCs still undergo long-term self-renewal and quiescence. Unlike apical NSCs, they are largely devoid of primary cilia and Prominin-1, Nestin and glial fibrillary acidic protein (GFAP) immunoreactivity. Six weeks after viral tagging of apical cells, few descendant cells were detected in the basal V-SVZ, including Sox9+ progenitors and GFAP+ astrocytes, and very rare new neurons in the OB, indicating that adult-born OB neurons originate from basal and not apical NSCs. Consistent with this, we found that pregnancy, a physiological modulator of adult OB neurogenesis, selectively increases the number of basal but not apical NSCs. Lastly, we find that apical NSCs display the highest levels of Notch activation in the neural lineage, and that selective apical downregulation of Notch-signaling effector Hes1 decreases Notch activation while increasing proliferation across the V-SVZ. Thus, apical NSCs act essentially as neurogenesis gatekeepers by modulating Notch-mediated lateral inhibition of proliferation in the adult V-SVZ.Graphical AbstractHighlightsBasal NSCs are the most abundant stem cell type in the adult V-SVZ from birth onwards.Apical and basal NSCs display distinct characteristics and cell cycle progression dynamics.Apical NSCs are not the main source of newly generated adult OB interneurons.Apical NSCs regulate intermediate progenitor proliferation by orchestrating Notch-mediated lateral inhibition.

show abstract

“…In addition, the C. elegans tll orthologue nhr-67 regulates both lin-12 (Notch) and lag-2 (Delta) during uterus development (Verghese et al, 2011). Strikingly, in the mouse brain, the tll orthologue Nr2E1 (aka Tlx ) was recently shown to negatively regulate the canonical Notch target gene Hes1 (Luque-Molina et al, 2019). Against this backdrop, it is tempting to speculate that the group NB delamination normally observed in the procephalic region results, at least in part from tll repression of the Notch pathway.…”

Section: Discussionmentioning

confidence: 99%

Anterior CNS expansion driven by brain transcription factors

Curt

Salmani

Thor

2019

eLife

View full text Add to dashboard Cite

During CNS development, there is prominent expansion of the anterior region, the brain. In Drosophila, anterior CNS expansion emerges from three rostral features: (1) increased progenitor cell generation, (2) extended progenitor cell proliferation, (3) more proliferative daughters. We find that tailless (mouse Nr2E1/Tlx), otp/Rx/hbn (Otp/Arx/Rax) and Doc1/2/3 (Tbx2/3/6) are important for brain progenitor generation. These genes, and earmuff (FezF1/2), are also important for subsequent progenitor and/or daughter cell proliferation in the brain. Brain TF co-misexpression can drive brain-profile proliferation in the nerve cord, and can reprogram developing wing discs into brain neural progenitors. Brain TF expression is promoted by the PRC2 complex, acting to keep the brain free of anti-proliferative and repressive action of Hox homeotic genes. Hence, anterior expansion of the Drosophila CNS is mediated by brain TF driven ‘super-generation’ of progenitors, as well as ‘hyper-proliferation’ of progenitor and daughter cells, promoted by PRC2-mediated repression of Hox activity.

show abstract

The Orphan Nuclear Receptor TLX Represses Hes1 Expression, Thereby Affecting NOTCH Signaling and Lineage Progression in the Adult SEZ

Cited by 10 publications

References 49 publications

Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life

Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life

A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

Anterior CNS expansion driven by brain transcription factors

Contact Info

Product

Resources

About