Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Journal of Pineal Research

et al. 2014

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Melatonin, a major pineal secretory product, exerts a range of physiological and neuroprotective effects. However, the functional significance of melatonin in determining neural identity, and the mechanisms by which this may occur, is unknown. In this study, P19 cells were used as a model system and cell behavior was monitored. Our data show that melatonin plays an important role in determining cell fate during neural commitment and promoting the differentiation of pluripotent P19 cells (Oct4(+) Sox2(+) ) into neural stem cells (Oct4(-) Sox2(+) ). This promotion appears to coincide with the activation of the MT1 receptor and phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2). Furthermore, our results show that melatonin regulates neural fate specification of P19 cells through two distinct mechanisms: the promotion of nuclear localization of ERK1/2 and upregulation of Sox2 transcription, and suppression of Smad1-induced expression of mesodermal-specific genes, such as Bra.

Section: Resultssupporting

confidence: 76%

“…Monolayer P19 cells are capable of differentiating into endoderm‐ and mesoderm‐like cells . As we observed, melatonin treatment of P19 cells significantly increased the number of Sox2‐positive cells during neural fate specification.…”

Section: Resultssupporting

confidence: 72%

Melatonin promotes the acquisition of neural identity through extracellular‐signal‐regulated kinases 1/2 activation

Journal of Pineal Research

et al. 2014

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“…Clinical phenotypes of mice lacking ZDHHC13 expression have been characterized in mice generated either by ethylnitrosourea mutagenesis (Saleem et al, 2010) or by direct and conditional knockout technologies (Chen et al, 2017a). A previous study on the role of ZDHHC13 in zebrafish embryonic development indicated that this protein could regulate ectoderm and mesoderm homeostasis via a PAT-independent mechanism (Chen et al, 2014). That finding prompted us to revisit the question of whether PAT enzymatic activity is indeed responsible for maintaining skin barrier integrity.…”

Section: Discussionmentioning

confidence: 99%

Palmitoyl Acyltransferase Activity of ZDHHC13 Regulates Skin Barrier Development Partly by Controlling PADi3 and TGM1 Protein Stability

Lin

Journal of Investigative Dermatology

et al. 2020

Deficiency of the palmitoyl-acyl transferase ZDHHC13 compromises skin barrier permeability and renders mice susceptible to environmental bacterial infection and inflammatory dermatitis. It had been unclear how the lack of ZDHHC13 proteins resulted in cutaneous abnormalities. In this study, we first demonstrate that enzymatic palmitoylation activity, rather than protein scaffolding, by ZDHHC13 is essential for skin barrier integrity, showing that knock-in mice bearing an enzymatically dead DQ-to-AA ZDHHC13 mutation lost their hair after weaning cyclically, recapitulating knockout phenotypes of skin inflammation and dermatitis. To establish the ZDHHC13 substrates responsible for skin barrier development, we employed quantitative proteomic approaches to identify protein molecules whose palmitoylation is tightly controlled by ZDHHC13. We identified over 300 candidate proteins that could be classified into four biological categories: immunological disease, skin development and function, dermatological disease, and lipid metabolism. Palmitoylation of three of these candidates-loricrin, peptidyl arginine deiminase type III, and keratin fiber crosslinker transglutaminase 1-by ZDHHC13 was confirmed by biochemical assay. Palmitoylation was critical for in vivo protein stability of the latter two candidates. Our findings reveal the importance of protein palmitoylation in skin barrier development, partly by promoting envelope protein crosslinking and the filaggrin processing pathway.

“…Western blot and Whole‐mount immunostaining were described previously (Chen et al, ; Shi et al, ). The primary antibodies were as follows: for Western blotting: anti‐ERK1/2 (1:1000; Cell Signaling Technology), anti‐p‐ERK1/2 (1:1000; Cell Signaling Technology) and anti‐β‐actin (1:2000, Sigma); for whole‐mount immunostaining: acetylated α‐tubulin (1:200; Sigma).…”

Section: Methodsmentioning

confidence: 99%

ZDHHC16 modulates FGF/ERK dependent proliferation of neural stem/progenitor cells in the zebrafish telencephalon

Shi

Developmental Neurobiology

Wang

et al. 2016

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In vertebrates, neural stem/progenitor cells (NSPCs) maintenance is critical for nervous system development and homeostasis. However, the molecular mechanisms underlying the maintenance of NSPCs have not been fully elucidated. Here, we demonstrated that zebrafish ZDHHC16, a DHHC encoding protein, which was related to protein palmitoylation after translation, was expressed in the developing forebrain, and especially in the telencephalon. Loss- and gain-of-function studies showed that ZDHHC16 played a crucial role in the regualtion of NSPCs proliferation during zebrafish telencephalic development, via a mechanism dependent on its palmitoyltransferase activity. Further analyses showed that the inhibition of ZDHHC16 led to inactivation of the FGF/ERK signaling pathway during telencephalic NSPCs proliferation and maintenance. Taken together, our results suggest that ZDHHC16 activity is essential for early NSPCs proliferation where it acts to activate the FGF/ERK network, allowing for the initiation of proliferation -regulated gene expression programs. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1014-1028, 2016.