Stage-specific roles of FGF2 signaling in human neural development.
This study elucidated the stage-specific roles of FGF2 signaling during neural development using in-vitro human embryonic stem cell-based developmental modeling. We found that the dysregulation of FGF2 signaling prior to the onset of neural induction resulted in the malformation of neural rosettes (a neural tube-like structure), despite cells having undergone neural induction. The aberrant neural rosette formation may be attributed to the misplacement of ZO-1, which is a polarized tight junction protein and shown co-localized with FGF2/FGFR1 in the apical region of neural rosettes, subsequently led to abnormal neurogenesis. Moreover, the FGF2 signaling inhibition at the stage of neural rosettes caused a reduction in cell proliferation, an increase in numbers of cells with cell-cycle exit, and premature neurogenesis. These effects may be mediated by NUMB, to which expression was observed enriched in the apical region of neural rosettes after FGF2 signaling inhibition coinciding with the disappearance of PAX6+/Ki67+neural stem cells and the emergence of MAP2+neurons. Moreover, our results suggested that the hESC-based developmental system reserved a similar neural stem cell niche in vivo.
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Marta
M
Grabiec
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Hana
H
Hříbková
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Miroslav
M
Vařecha
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Dana
D
Střítecká
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Aleš
A
Hampl
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Petr
P
Dvořák
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. Electronic address: wadeley@med.muni.cz.
Yuh-Man
YM
Sun
D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D059008:Time-Lapse Imaging; D062826:Zonula Occludens-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D002867:Chromones; C489788:MAP2 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C115711:PD 173074; D011743:Pyrimidines; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D016222:Fibroblast Growth Factor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051496:Receptor, Fibroblast Growth Factor, Type 1
Embryonic stem cells; FGF2 signaling; Neural developmental modeling; Neural fate; Neural stem cell niche; Neurogenesis