Retinal Muller glia play a critical role in regulating the survival of retinal neurons following damage, and may be a useful source for cell-based regenerative therapies for retinal dystrophies. Over the past few years, we have established the progenitor and glial-expressed homeodomain transcription factor Lhx2 as an essential regulator of multiple different aspects of Muller glial development and function. In neonatal retinal progenitors, Lhx2 promotes neurogenesis at the expense of gliogenesis, but Lhx2 is essential for glial differentiation when expressed in postmitotic glial precursors. Lhx2 also functions in terminally differentiated Muller glia to both repress expression of genes induced in hypertrophic gliosis and promote expression of glial-derived neuroprotective factors following injury.
We aim to investigate the molecular mechanisms that allow Lhx2 to perform this diverse range of regulatory functions.
We aim to comprehensively profile Lhx2 DNA binding patterns in retinal progenitors, glial precursors and in mature resting and reactive Muller glia. We will use this data together with mRNA expression data from these cell types to identify candidate cofactors that selectively and differentially regulate Lhx2 function, and confirm this using both in vivo electroporation and targeted genetic approaches. We ultimately intend to use these findings to determine if glial dedifferentiation can be induced, or the neuroprotective functions of retinal gla enhanced, by manipulating Lhx2 activity.

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Retinal Muller glia are critical for maintaining photoreceptor survival following damage, and may also be a potential source for regeneration of photoreceptors lost in disease. We have identified the Lhx2 gene as a key molecular player in regulating both the development of Muller glia and their response to injury, and propose to investigate how Lhx2 is able to perform these functions. We expect that this work may reveal new approaches to controlling Muller glial function in diseased retina and restoring function of damaged photoreceptors.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (BVS)
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Greenwell, Thomas
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Johns Hopkins University
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de Melo, Jimmy; Blackshaw, Seth (2018) In Vivo Electroporation of Developing Mouse Retina. Methods Mol Biol 1715:101-111
de Melo, Jimmy; Clark, Brian S; Venkataraman, Anand et al. (2018) Ldb1- and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in the retina. Development 145:
Remez, Liv Aleen; Onishi, Akishi; Menuchin-Lasowski, Yotam et al. (2017) Pax6 is essential for the generation of late-born retinal neurons and for inhibition of photoreceptor-fate during late stages of retinogenesis. Dev Biol 432:140-150
Clark, Brian S; Blackshaw, Seth (2017) Understanding the Role of lncRNAs in Nervous System Development. Adv Exp Med Biol 1008:253-282
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de Melo, Jimmy; Clark, Brian S; Blackshaw, Seth (2016) Multiple intrinsic factors act in concert with Lhx2 to direct retinal gliogenesis. Sci Rep 6:32757
Thein, Thuzar; de Melo, Jimmy; Zibetti, Cristina et al. (2016) Control of lens development by Lhx2-regulated neuroretinal FGFs. Development 143:3994-4002
de Melo, Jimmy; Zibetti, Cristina; Clark, Brian S et al. (2016) Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling. J Neurosci 36:2391-405
Mattar, Pierre; Ericson, Johan; Blackshaw, Seth et al. (2015) A conserved regulatory logic controls temporal identity in mouse neural progenitors. Neuron 85:497-504

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