Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development.
Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells derive from a previously neurogenic region of the inner ear. The related bHLH genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and sensory epithelial development in this system. Our analysis of mouse mutants indicates that a mutual antagonism between Ngn1 and Math1 regulates the transition from neurogenesis to sensory cell production during ear development. Furthermore, we provide evidence that the transition to sensory cell production involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1 (positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an uncommitted progenitor cell population through Notch-mediated lateral inhibition, and Math1 irreversibly commits these progenitors to a hair-cell fate.
Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 West 3rd Street, Los Angeles CA 90057, USA.
Steven
S
Raft
Edmund J
EJ
Koundakjian
Herson
H
Quinones
Chathurani S
CS
Jayasena
Lisa V
LV
Goodrich
Jane E
JE
Johnson
Neil
N
Segil
Andrew K
AK
Groves
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D007758:Ear, Inner / Q000166:cytology / Q000196:embryology* / Q000294:innervation / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D006198:Hair Cells, Auditory / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D051880:Receptors, Notch / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012444:Saccule and Utricle / Q000166:cytology / Q000196:embryology / Q000294:innervation / Q000378:metabolism; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C500943:Atoh1 protein, mouse; C486336:Neurog1 protein, mouse