title: Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling.
abstract: Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data support a model in which Tfap2a, acting through Bmp7a, modulates Fgf and Notch signaling to control the duration, amount and speed of SAG neural development.
authors.affiliation: Biology Department, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Husniye
authors.initials: H
authors.lastname: Kantarci
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Renee K
authors.initials: RK
authors.lastname: Edlund
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Groves
authors.affiliation: Biology Department, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Riley
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002645:Chickens; D007758:Ear, Inner / Q000254:growth & development / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D045888:Ganglion Cysts / Q000196:embryology / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055495:Neurogenesis / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000096:biosynthesis* / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D055419:Bone Morphogenetic Protein 7; D051880:Receptors, Notch; D050656:Transcription Factor AP-2; D029961:Zebrafish Proteins; C525826:bmp7a protein, zebrafish; C493676:tfap2a protein, zebrafish; D005346:Fibroblast Growth Factors