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    • Lastly some targets of Foxd are also required

    2018-11-12

    Lastly, some targets of Foxd3 are also required to prevent aberrant apoptosis. Safb indirectly represses apoptotic genes in breast cancer po1 (Lee et al., 2007; Chan et al., 2007). Therefore, decreased Safb expression in Foxd3 mutant ESCs may lead to an increase in apoptosis. Finally, Pmaip1 (also called Noxa) is a direct target of Foxd3 and is a critical regulator of cell death. Pmaip1 is required for the activation of caspases and contributes to p53-dependent apoptosis (Li et al., 2006; Oda et al., 2000; Yakovlev et al., 2004). The following are the supplementary data related to this article.
    Acknowledgments We thank Adam Bazinet and Drs. Steve Dalton and Ali Brivanlou for their careful reading of this manuscript. P.A.L. was supported by NIHR01HD036720, a pilot grant from NIH 5P01GM085354, and the Vanderbilt University Medical Center Academic Support program. J.L.P. was supported by AHA10PRE4500024. M.T.S. was supported by NIH T32HD007043. C.L.G. was supported by NIH U01HL100398.
    Introduction Sensorineural hearing loss occurs when the delicate sensory hair cells of the inner ear are injured by factors such as loud noise, trauma, and exposure to ototoxic compounds or simply ageing. Currently, the principal treatment for sensorineural hearing loss is a cochlear implant. This device reinstates the transmission of sound information to the central auditory pathway by providing direct electrical stimulation to the primary auditory neurons (in the absence of hair cells; Seligman and Shepherd, 2004). This neural population provides the critical link between the peripheral cochlea and the central auditory system, and auditory neurons are capable of responding to high stimulation rates with temporal acuity (Kiang et al., 1965; Javel and Viemeister, 2000). Importantly, while the cochlear implant relies upon a functional population of primary auditory neurons to convey auditory input to higher neural centers, these auditory neurons themselves are often vulnerable to degeneration after hearing loss, or may even be the site of primary damage. An extensive loss of primary auditory neurons is assumed to significantly reduce the effectiveness of a cochlear implant. Stem cells offer an opportunity to restore auditory function by replacing lost auditory neurons in cases of severe depletion. A number of studies have now demonstrated the potential of stem cells to differentiate into appropriate neurosensory progenitors, including those of human origin (Shi et al., 2007; Chen et al., 2009, 2012; Nayagam et al., 2013). The expression of key developmental markers in the differentiation of human stem cells toward an auditory neural lineage has recently been documented (Chen et al., 2012; and reviewed by Gunewardene et al., 2012) and includes the expression of key proteins and transcription factors Sox 2, Pax2/8, FoxG1, Six1, Nestin and Brn3a (Chen et al., 2012), Brn3a, GATA3 and peripherin (Shi et al., 2007), Pax2, Brn3a, peripherin, and neurofilament (Nayagam et al., 2013) and NeuroD1, Brn3a, GATA3, Islet1, peripherin, and neurofilament (Gunewardene et al., 2013). The method used to generate sensory neurons in the present study is based on previously published protocols from our laboratories for deriving neural crest progenitors (Holt et al., 2006; Denham and Dottori, 2011; Liu et al., 2011; Nayagam et al., 2013). Recent literature supports the use of neural crest progenitors in a cell replacement therapy for deafness, given the molecular similarity of this population to placode-derived sensory neurons (Huisman and Rivolta, 2012; Nayagam et al., 2013). In addition, we have recently demonstrated that neurons derived from this induction protocol express key auditory neural proteins including NeuroD1, Brn3a, GATA3, Islet1 and neurofilament (Fig. 1; Gunewardene et al., 2013) and are capable of making synapses on developing mammalian hair cells in vitro (Nayagam et al., 2013). Given that neural crest progenitors can also be readily obtained from adults (Yang and Xu, 2013), they have the potential to facilitate the development of patient-matched cell transplants in the future (Huisman and Rivolta, 2012; Yang and Xu, 2013).