Efficient derivation of functional floor plate tissue from human embryonic stem cells.
The floor plate (FP) is a critical signaling center during neural development located along the ventral midline of the embryo. Little is known about human FP development because of the lack of tissue accessibility. Here we report the efficient derivation of human embryonic stem cell (hESC)-derived FP tissue capable of secreting Netrin-1 and SHH and patterning primary and hESC derived tissues. FP induction in hESCs is dependent on early SHH exposure and occurs at the expense of anterior neurectoderm (AN). Global gene expression and functional studies identify SHH-mediated inhibition of Dkk-1 as key factor in FP versus AN specification. hESC-derived FP tissue is shown to be of anterior SIX6+ character but is responsive to caudalizing factors suppressing SIX6 expression and inducing a shift in usage of region-specific SHH enhancers. These data define the early signals that drive human FP versus AN specification and determine regional identity in hESC-derived FP.
Fasano
Christopher A
CA
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA; New York Neural Stem Cell Institute, Rensselaer, NY 12144, USA. Electronic address: chrisfasano@nynsci.org.
Chambers
Stuart M
SM
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA.
Lee
Gabsang
G
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA.
Tomishima
Mark J
MJ
SKI Stem Cell Research Facility, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA.
Studer
Lorenz
L
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA; Department of Neurosurgery, Sloan-Kettering Institute, 1275 York Ave, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.
D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009420:Nervous System / Q000166:cytology* / Q000378:metabolism; D054258:Neural Plate / Q000196:embryology / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
C501126:DKK1 protein, human; C496502:FOXA2 protein, human; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C509239:SHH protein, human; D051542:Hepatocyte Nuclear Factor 3-beta