Our long-term objective in the proposed experiments is to obtain new knowledge on the basic mechanisms that control retinal development and to apply this knowledge to develop novel ways to treat retinal degenerative diseases. Our strategy is to use genetically engineered mouse models that we have already created or that we will create. Although an impressive amount of information has accumulated on the mechanisms that control retinal development, large gaps still remain. In particular, the mechanisms that control a progenitor cell's decision whether to proliferate or differentiate are only vaguely understood. A better understanding is of great importance for finding new ways to repair damaged retinas. Retinal ganglion cells (RGCs) are the first cell type to differentiate from retinal progenitor cells (RPCs) during development and are the retinal neurons that connect to the brain. We focus on the regulatory events that cause RPCs to commit to a RGC fate. In related experiments, embryonic RPCs will be used to repopulate RGCs in adult retinas that have been depleted of their endogenous RGCs. Our underlying hypothesis is that for RPCs to differentiate into RGCs, Atoh7 must integrate with other regulatory factors to achieve a balance between proliferation and differentiation. To address the hypothesis, we proposed three specific aims.
The first aim will determine whether Atoh7 is sufficient to convert non-RGCs to a RGC fate. Preliminary work indicates that replacing Neurod1 with Atoh7 leads to ectopic RGC gene expression in the inner nuclear layer. We will determine whether Atoh7 can drive RGC differentiation in non-RGC neurons in developing and adult retinas.
The second aim will determine whether Atoh7 regulates Notch signaling to control the balance between RPC proliferation and RGC commitment. In preliminary experiments, we found that Atoh7 binds to E-box elements upstream of Notch1 and that Atoh7 negatively regulates Notch1 expression. We will identify the time at which Atoh7 appears relative to Notch signaling. We will determine whether Atoh7 and Notch1 participate in a negative feedback loop and whether RPC proliferation is perturbed when the Atoh7 binding sites on Notch1 are deleted. In the third aim, we will optimize our experiments on repopulating RGC-depleted retinas by transplanting Atoh7-expressing RPCs into the retinas of RGC-depleted mice along with neuroprotective factors. We will also determine whether Atoh7-expressing RPCs can regenerate optic nerves in optic nerve crush and other mouse models. Our knowledge of the factors controlling retinal development allows us to apply developmental concepts to adult retinas. We have developed realistic genetic models for human optic nerve degeneration that will have ultimate use in stem cell replacement therapy to repair damaged optic nerves.
In order to understand the fundamental genetic programs controlling the advancement of a multipotent neural progenitor cell to a terminally differentiated neuron, we study retinal progenitor cells that are programmed to differentiate into retinal ganglion cells. We use genetically engineered mice coupled with strategies to elucidate the retinal ganglion cell gene regulatory network, and in addition, we develop realistic genetic models for human optic nerve degeneration for ultimate use in stem cell replacement therapy to restore retinal ganglion cells and regenerate damaged optic nerves.
|Mao, Chai-An; Agca, Cavit; Mocko-Strand, Julie A et al. (2016) Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development. Proc Biol Sci 283:20152978|
|Gao, Zhiguang; Mao, Chai-An; Pan, Ping et al. (2014) Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7-dependent regulatory genes for retinal ganglion cell formation. Dev Neurobiol 74:1123-40|
|Nowotschin, Sonja; Costello, Ita; Piliszek, Anna et al. (2013) The T-box transcription factor Eomesodermin is essential for AVE induction in the mouse embryo. Genes Dev 27:997-1002|
|Mandal, Nawajes A; Tran, Julie-Thu A; Saadi, Anisse et al. (2013) Expression and localization of CERKL in the mammalian retina, its response to light-stress, and relationship with NeuroD1 gene. Exp Eye Res 106:24-33|
|Mao, Chai-An; Cho, Jang-Hyeon; Wang, Jing et al. (2013) Reprogramming amacrine and photoreceptor progenitors into retinal ganglion cells by replacing Neurod1 with Atoh7. Development 140:541-51|
|Wang, Jianbo; Sun, Zhao; Zhang, Zichao et al. (2013) Protein inhibitors of activated STAT (Pias1 and Piasy) differentially regulate pituitary homeobox 2 (PITX2) transcriptional activity. J Biol Chem 288:12580-95|
|Ehrman, Lisa A; Mu, Xiuqian; Waclaw, Ronald R et al. (2013) The LIM homeobox gene Isl1 is required for the correct development of the striatonigral pathway in the mouse. Proc Natl Acad Sci U S A 110:E4026-35|
|Mizuguchi, Rumiko; Naritsuka, Hiromi; Mori, Kensaku et al. (2012) Tbr2 deficiency in mitral and tufted cells disrupts excitatory-inhibitory balance of neural circuitry in the mouse olfactory bulb. J Neurosci 32:8831-44|
|Kiyama, Takae; Mao, Chai-An; Cho, Jang-Hyeon et al. (2011) Overlapping spatiotemporal patterns of regulatory gene expression are required for neuronal progenitors to specify retinal ganglion cell fate. Vision Res 51:251-9|
|Liu, Pu; Fu, Xueyao; Johnson, Randy L (2011) Efficient in vivo doxycycline and cre recombinase-mediated inducible transgene activation in the murine trabecular meshwork. Invest Ophthalmol Vis Sci 52:969-74|
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