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Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

ABSTRACT: Neural induction is the first step in the formation of the vertebrate central nervous system. The emerging consensus of the mechanisms underlying neural induction is the combined influences from inhibiting bone morphogenetic protein (BMP) signaling and activating fibroblast growth factor (FGF)/Erk signaling, which act extrinsically via either autocrine or paracrine fashions. However, do intrinsic forces (cues) exist and do they play decisive roles in neural induction? These questions remain to be answered. Here, we have identified a novel neural initiator, neuronatin (Nnat), which acts as an intrinsic factor to promote neural fate in mammals and Xenopus. ESCs lacking this intrinsic factor fail to undergo neural induction despite the inhibition of the BMP pathway. We show that Nnat initiates neural induction in ESCs through increasing intracellular Ca(2+) ([Ca(2+) ](i)) by antagonizing Ca(2+) -ATPase isoform 2 (sarco/endoplasmic reticulum Ca(2+) -ATPase isoform 2) in the endoplasmic reticulum, which in turn increases the phosphorylation of Erk1/2 and inhibits the BMP4 pathway and leads to neural induction in conjunction with FGF/Erk pathway.

SUBMITTER: Lin HH

PROVIDER: S-EPMC3003906 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

Lin Hsuan-Hwai HH Bell Esther E Uwanogho Dafe D Perfect Leo W LW Noristani Harun H Bates Thomas J D TJ Snetkov Vladimir V Price Jack J Sun Yuh-Man YM

Stem cells (Dayton, Ohio) 20101101 11

Neural induction is the first step in the formation of the vertebrate central nervous system. The emerging consensus of the mechanisms underlying neural induction is the combined influences from inhibiting bone morphogenetic protein (BMP) signaling and activating fibroblast growth factor (FGF)/Erk signaling, which act extrinsically via either autocrine or paracrine fashions. However, do intrinsic forces (cues) exist and do they play decisive roles in neural induction? These questions remain to b ...[more]

PMID: 20872847

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Project description:BACKGROUND:Lymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LT? binds one or two membrane-associated LT? to form LT?2?1 or LT?1?2 heterotrimers. The predominant LT?1?2 binds to LT? receptor (LT?R) primarily expressed in epithelial and stromal cells. Most studies on LT?R signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LT?R signaling in the nervous system, particularly in neurogenesis, remain unknown. Here, we investigated the role of LT?R-mediated NF?B signaling in regulating neural lineage differentiation. METHODS:The C57BL/6J wild-type and GFAP-dnI?B? transgenic mice were used. Serum-free embryoid bodies were cultured from mouse embryonic stem cells and further induced into neural stem/progenitor cells (NSCs/NPCs). Primary neurospheres were cultured from embryonic and adult mouse brains followed by monolayer culture for amplification/passage. NF?B activation was determined by adenovirus-mediated NF?B-firefly-luciferase reporter assay and p65/RelB/p52 nuclear translocation assay. LT?R mRNA expression was evaluated by quantitative RT-PCR and LT?R protein expression was determined by immunohistochemistry and Western blot analysis. Multilabeled immunocytochemistry or immunohistochemistry followed by fluorescent confocal microscopy and quantitative analysis of neural lineage differentiation were performed. Graphing and statistical analysis were performed with GraphPad Prism software. RESULTS:In cultured NSCs/NPCs, LT?1?2 stimulation induced an activation of classical and non-classical NF?B signaling. The expression of LT?R-like immunoreactivity in GFAP+/Sox2+ NSCs was identified in well-established neurogenic zones of adult mouse brain. Quantitative RT-PCR and Western blot analysis validated the expression of LT?R in cultured NSCs/NPCs and brain neurogenic regions. LT?R expression was significantly increased during neural induction. LT?1?2 stimulation in cultured NSCs/NPCs promoted astroglial and oligodendrocytic lineage differentiation, but inhibited neuronal lineage differentiation. Astroglial NF?B inactivation in GFAP-dnI?B? transgenic mice rescued LT?R-mediated abnormal phenotypes of cultured NSCs/NPCs. CONCLUSION:This study provides the first evidence for the expression and function of LT?R signaling in NSCs/NPCs. Activation of LT?R signaling promotes glial lineage differentiation. Our results suggest that neurogenesis is regulated by the adaptive immunity and inflammatory responses.

Dataset Information

Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

Publications

Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

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