Tfap2a Promotes Specification and Maturation of Neurons in the Inner Ear through Modulation of Bmp, Fgf and Notch Signaling

Autor: Renée K. Edlund, Bruce B. Riley, Andrew K. Groves, Husniye Kantarci
Rok vydání: 2015
Předmět:
Cancer Research
medicine.medical_specialty
animal structures
lcsh:QH426-470
Bone Morphogenetic Protein 7
Neurogenesis
Cellular differentiation
Notch signaling pathway
Biology
Fibroblast growth factor
FGF and mesoderm formation
03 medical and health sciences
0302 clinical medicine
Neuroblast
Internal medicine
parasitic diseases
Genetics
medicine
Animals
Molecular Biology
Zebrafish
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Ganglion Cysts
0303 health sciences
Receptors
Notch
Gene Expression Regulation
Developmental
Cell Differentiation
Zebrafish Proteins
Cell biology
Fibroblast Growth Factors
body regions
lcsh:Genetics
Endocrinology
Transcription Factor AP-2
Ear
Inner
Otic vesicle
Chickens
Neural development
030217 neurology & neurosurgery
Signal Transduction
Research Article
Zdroj: PLoS Genetics, Vol 11, Iss 3, p e1005037 (2015)
PLoS Genetics
ISSN: 1553-7404
Popis: 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.
Author Summary Neurons of the statoacoustic ganglion (SAG) transmit impulses from the inner ear necessary for hearing and balance. SAG cells exhibit a complex pattern of development, regulation of which remains poorly understood. Here we show that transcription factor Tfap2a coordinates multiple cell signaling pathways needed to regulate the quantity and pace of SAG neuron production. SAG progenitors originate within the developing inner ear and then migrate out of the ear towards the hindbrain before forming mature neurons. We showed previously that Fgf initiates formation of SAG progenitors in the inner ear, but rising levels of Fgf signaling eventually terminate this process. Elevated Fgf also stimulates proliferation of SAG progenitors outside the ear and delays their maturation. Notch signaling is also known to limit SAG development. Tfap2a governs the strength of Fgf and Notch signaling by activating expression of Bmp7a, which inhibits Fgf and Notch. Together these signals stabilize the pool of SAG progenitors outside the ear by equalizing rates of maturation and proliferation. This balance is critical for sustained accumulation of SAG neurons during larval growth as well as regeneration following neural damage. These findings could inform development of stem cell therapies to correct auditory neuropathies in humans.
Databáze: OpenAIRE
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