Critical role of type 2 ryanodine receptor in mediating activity-dependent neurogenesis from embryonic stem cells.
Activity-induced neurogenesis via Ca(2+) entry may be important for establishing Hebbian neural network. However, it remains unclear whether intracellular Ca(2+) mobilization is required and which subtypes of Ca(2+) release channels expressed in Ca(2+) store organelles are involved in the activity-dependent neurogenesis. Here, we demonstrated that the activity of intracellular Ca(2+) signaling, expression of neuronal transcription factor NeuroD, and the rate of neurogenesis were significantly inhibited in neuronal cells derived from embryonic stem (ES) cells deficient in the Ca(2+) release channel type 2 ryanodine receptors (RyR2(-/-)). In wild-type (RyR2(+/+)) but not in RyR2(-/-) ES cells, activation of L-type Ca(2+) channels, GABA(A) receptors, or RyRs promoted neuronal differentiation, while inhibition of these channels/receptors had an opposite effect. Moreover, neuronal differentiation promoted by activation of GABA(A) receptors or L-type Ca(2+) channels in RyR2(+/+) cells was prevented by RyR inhibitors. No significant difference was detected in the expression level of GABA(A) receptors and L-type channels between neuronal cells derived from two types of ES cells. Thus, activity-induced Ca(2+) influx through L-type Ca(2+) channels alone is not sufficient in promoting neurogenesis. Instead, an intimate cooperation of L-type Ca(2+) channels with RyR2 is crucial for the activity-dependent neurogenesis induced by paracrine and/or autocrine GABA signaling.
Yu
Hui-Mei
HM
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
Wen
Jing
J
Wang
Rong
R
Shen
Wan-Hua
WH
Duan
Shumin
S
Yang
Huang-Tian
HT
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D017353:Gene Deletion; D051379:Mice; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*
D020746:Calcium Channels, L-Type; D011963:Receptors, GABA-A; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium