Myb promotes centriole amplification and later steps of the multiciliogenesis program.
The transcriptional control of primary cilium formation and ciliary motility are beginning to be understood, but little is known about the transcriptional programs that control cilium number and other structural and functional specializations. One of the most intriguing ciliary specializations occurs in multiciliated cells (MCCs), which amplify their centrioles to nucleate hundreds of cilia per cell, instead of the usual monocilium. Here we report that the transcription factor MYB, which promotes S phase and drives cycling of a variety of progenitor cells, is expressed in postmitotic epithelial cells of the mouse airways and ependyma destined to become MCCs. MYB is expressed early in multiciliogenesis, as progenitors exit the cell cycle and amplify their centrioles, then switches off as MCCs mature. Conditional inactivation of Myb in the developing airways blocks or delays centriole amplification and expression of FOXJ1, a transcription factor that controls centriole docking and ciliary motility, and airways fail to become fully ciliated. We provide evidence that MYB acts in a conserved pathway downstream of Notch signaling and multicilin, a protein related to the S-phase regulator geminin, and upstream of FOXJ1. MYB can activate endogenous Foxj1 expression and stimulate a cotransfected Foxj1 reporter in heterologous cells, and it can drive the complete multiciliogenesis program in Xenopus embryonic epidermis. We conclude that MYB has an early, crucial and conserved role in multiciliogenesis, and propose that it promotes a novel S-like phase in which centriole amplification occurs uncoupled from DNA synthesis, and then drives later steps of multiciliogenesis through induction of Foxj1.
Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Fraser E
FE
Tan
Eszter K
EK
Vladar
Lina
L
Ma
Luis C
LC
Fuentealba
Ramona
R
Hoh
F Hernán
FH
Espinoza
Jeffrey D
JD
Axelrod
Arturo
A
Alvarez-Buylla
Tim
T
Stearns
Chris
C
Kintner
Mark A
MA
Krasnow
D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D002502:Centrioles / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D004805:Ependyma / Q000196:embryology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D008168:Lung / Q000196:embryology / Q000378:metabolism; D051379:Mice / Q000196:embryology; D008822:Mice, Transgenic; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D015398:Signal Transduction; D014132:Trachea / Q000196:embryology / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology
C481963:FOXJ1 protein, mouse; D051858:Forkhead Transcription Factors; D020598:Proto-Oncogene Proteins c-myb
Centriole amplification; Multiciliogenesis; Myb