Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis.
In many regions of the developing CNS, distinct cell types are born at different times. The means by which discrete and stereotyped temporal switches in cellular identities are acquired remains poorly understood. To address this, we have examined how visceral motor neurons (VMNs) and serotonergic neurons, two neuronal subtypes, are sequentially generated from a common progenitor pool in the vertebrate hindbrain. We found that the forkhead transcription factor Foxa2, acting in progenitors, is essential for the transition from VMN to serotonergic neurogenesis. Loss-of-function and gain-of-function experiments indicated that Foxa2 activates the switch through a temporal cross-repressive interaction with paired-like homeobox 2b (Phox2b), the VMN progenitor determinant. This mechanism bears a marked resemblance to the cross-repression between neighboring domains of transcription factors that establish discrete progenitor identities along the spatial axes. Moreover, the subsequent differentiation of central serotonergic neurons required both the suppression of VMN neurogenesis and the induction of downstream intrinsic determinants of serotonergic identity by Foxa2.
Jacob
John
J
Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Ferri
Anna L
AL
Milton
Christopher
C
Prin
Fabrice
F
Pla
Patrick
P
Lin
Wei
W
Gavalas
Anthony
A
Ang
Siew-Lan
SL
Briscoe
James
J
D000367:Age Factors; D000818:Animals; D019521:Body Patterning / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002642:Chick Embryo; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
C496503:Foxa2 protein, mouse; D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D012701:Serotonin; D001973:Bromodeoxyuridine