Msi2 Maintains Quiescent State of Hair Follicle Stem Cells by Directly Repressing the Hh Signaling Pathway

Ma, Xianghui; Tian, Ye; Song, Yongli; Shi, Jianyun; Xu, Jiuzhi; Xiong, Kai; Li, Jia; Xu, Wenjie; Zhao, Yaofeng; Shuai, Jianwei; Chen, Lei; Plikus, Maksim V.; Lengner, Christopher J.; Ren, Fazheng; Xue, Lixiang; Yu, Zhengquan

doi:10.1016/j.jid.2017.01.012

Cited by 34 publications

(30 citation statements)

References 44 publications

(88 reference statements)

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“…Small molecule agonist SAG binds Smo directly and bypasses Patched receptors to activate Shh signaling. Topical application of SAG has been demonstrated to stimulate the hair regrowth in adult mouse skin . To ascertain whether direct activation of Smo can rescue HF phenotypes in Hes1 eKO mice, we performed transient application of vehicle and SAG at opposite sides of the back skin during repetitive depilation (Figures A and S6A).…”

Section: Resultsmentioning

confidence: 99%

Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling

Suen

Yang

2019

Stem Cells

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Adult hair follicles undergo repeated cycling of regression (catagen), resting (telogen), and growth (anagen), which is maintained by hair follicle stem cells (HFSCs). The mechanism underlying hair growth initiation and HFSC maintenance is not fully understood. Here, by epithelial deletion of Hes1, a major Notch downstream transcriptional repressor, we found that hair growth is retarded, but the hair cycle progresses normally. Hes1 is specifically upregulated in the lower bulge/HG during anagen initiation. Accordingly, loss of Hes1 results in delayed activation of the secondary hair germ (HG) and shortened anagen phase. This developmental delay causes reduced hair shaft length but not identity changes in follicular lineages. Remarkably, Hes1 ablation results in impaired hair regeneration upon repetitive depilation. Microarray gene profiling on HFSCs indicates that Hes1 modulates Shh responsiveness in anagen initiation. Using primary keratinocyte cultures, we demonstrated that Hes1 deletion negatively influences ciliogenesis and Smoothened ciliary accumulation upon Shh treatment. Furthermore, transient application of Smoothened agonist duringrepetitive depilation can rescue anagen initiation and HFSC self-renewal in Hes1deficient hair follicles. We reveal a critical function of Hes1 in potentiating Shh signaling in anagen initiation, which allows sufficient signaling strength to expand the HG and replenish HFSCs to maintain the hair cycle homeostasis.

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Section: Resultsmentioning

confidence: 99%

Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling

Suen

Yang

2019

Stem Cells

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“…The mRNA altered by Msi2 KO, KD, and OE has been described in several tissues: skin (Bennett et al, 2016; Ma et al, 2017), intestinal epithelium (Wang et al, 2015), hematopoietic stem cells (Park et al, 2014; Rentas et al, 2016; Kharas and Lengner, 2017). As summarized in Table 3, these studies describe MSI2 effects on cell differentiation, migration, and cell‐cell interactions that may be relevant to any neurogenesis or circuit remodeling in the SCN.…”

Section: Discussionmentioning

confidence: 99%

Musashi‐2 and related stem cell proteins in the mouse suprachiasmatic nucleus and their potential role in circadian rhythms

Beligala

Malik

et al. 2019

Intl J of Devlp Neuroscience

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Background The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus contains the master circadian clock of the body and an unusually large number of cells expressing stem cell‐related proteins. These seemingly undifferentiated cells may serve in entrainment of the SCN circadian clock to light cycles or allow it to undergo neural plasticity important for modifying its rhythmic output signals. These cells may also proliferate and differentiate into neurons or glia in response to episodic stimuli or developmental events requiring alterations in the SCN's control of physiology and behavior. Problem To characterize expression of stem cell related proteins in the SCN and the effects of stem‐like cells on circadian rhythms. Methods Explant cultures of mouse SCN were maintained in medium designed to promote survival and growth of stem cells but not neuronal cells. Several stem cell marker proteins including SRY‐box containing gene 2 (SOX2), nestin, vimentin, octamer‐binding protein 4 (OCT4), and Musashi RNA‐binding protein 2 (MSI2) were identified by immunocytochemistry in histological sections from adult mouse SCN and in cultures of microdissected SCN. A bioinformatics analysis located potential SCN targets of MSI2 and related RNA‐binding proteins. Results Cells expressing stem cell markers proliferated in culture. Immunostained brain sections and bioinformatics supported the view that MSI2 regulates immature properties of SCN neurons, potentially providing flexibility in SCN neural circuits. Explant cultures had ongoing mitotic activity, indicated by proliferating‐cell nuclear antigen, and extensive cell loss shown by propidium iodide staining. Cells positive for vasoactive intestinal polypeptide (VIP) that are highly enriched in the SCN were diminished in explant cultures. Despite neuronal cell loss, tissue remained viable for over 7 weeks in culture, as shown by bioluminescence imaging of explants prepared from SCN of Per1::luc transgenic mice. The circadian rhythm in SCN gene expression persisted in brain slice cultures in stem cell medium. Prominent, widespread expression of RNA‐binding protein MSI2 supported the importance of posttranscriptional regulation in SCN functions and provided further evidence of stem‐like cells. Conclusion The results show that the SCN retains properties of immature neurons and these properties persist in culture conditions suitable for stem cells, where the SCN stem‐like cells also proliferate. These properties may allow adaptive circadian rhythm adjustments. Further exploration should examine stem‐like cells of the SCN in vivo, how they may affect circadian rhythms, and whether MSI2 serves as a master regulator of SCN stem‐like properties.

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“…) . Shh was the direct target of RNA‐binding proteins of Musashi (Msi)2 in the HF and Msi2 repressed Hh signalling activity, downregulated the expression of downstream Hh target genes Shh, Gli1 and Ptch2 , delayed hair growth and maintained a quiescent state of HFSCs in the process of telogen‐to‐anagen transition . Other molecular signalling pathways implicated in HF cycling are beyond the scope of this article (reviewed in Stenn and Paus) …”

Section: Molecular Signalling In Hair Follicle Development and Cyclinmentioning

confidence: 99%

From basal cell carcinoma morphogenesis to the alopecia induced by hedgehog inhibitors: connecting the dots

2017

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The deciphering of the hedgehog (Hh) signalling pathway implicated in the tumorigenesis of basal cell carcinoma (BCC) led to the development of targeted drug therapies, the Hh pathway inhibitors (HPIs) vismodegib and sonidegib. In the skin, physiological Hh signalling is activated in growing hair follicles (HFs), where it is required for proliferation of the epithelium of HFs during morphogenesis and for their postnatal growth. The effects of HPI treatment leading to the regression of BCC and the development of alopecia underpin the central role of the Hh pathway in BCC formation, as well as hair cycling. Given the fact that BCC is a follicular-driven tumour, it is a fine tuning of events that regulate hair cycling that may drive towards the formation of benign follicular hamartomas or malignant BCC neoplasms. Wnt/β-catenin signalling interacts with the Hh signalling during HF morphogenesis, normal hair cycling and BCC development. The aim of this review is to present how key molecular events implicated in Hh pathway crosstalk in the HF are also involved in BCC pathogenesis and result in the alopecia developed by HPI treatment.

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Msi2 Maintains Quiescent State of Hair Follicle Stem Cells by Directly Repressing the Hh Signaling Pathway

Cited by 34 publications

References 44 publications

Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling

Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling

Musashi‐2 and related stem cell proteins in the mouse suprachiasmatic nucleus and their potential role in circadian rhythms

From basal cell carcinoma morphogenesis to the alopecia induced by hedgehog inhibitors: connecting the dots

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