The mammalian retina is a highly ordered laminar tissue that detects, processes and relays all visual information from the eyes to the brain. It contains seven major cell types, including rod and cone photoreceptors, neurons, and glia, which derive from a mitotic multipotent progenitor pool. The process of cell fate specification is incompletely understood, but is known to depend on basic helix-loop-helix (bHLH) and homeodomain transcription factors (intrinsic), and intracellular signaling pathways (extrinsic). A small group of neurons, termed retinal ganglion cells (RGCs), differentiate first, and project axons to the central nervous system, forming the optic nerves. We are characterizing the functions of Math5 (Atoh7), a bHLH factor that is transiently expressed in the retina during the terminal cell cycle and is required for RGC development. These studies involve analysis of mutant mice and blind humans who is required lack optic nerves, BAC and conventional transgenes, specific manipulation of Notch and other signaling pathways, and retinal explant cultures.
Specifically, we are investigating:
- What are the molecular and cellular mechanisms of RGC histogenesis?
- What factors are required for RGC development, in addition to Math5?
- What sequences and factors regulate Math5 gene expression, and thus the onset of retinal neurogenesis?
- What symmetry rules control Math5 action and RGC fate between daughter cells?
In addition to the neural retina, the eye contains the pigmented epithelium (RPE), lens, anterior segment structures, and periocular mesenchyme. These tissues are patterned from the embryonic optic cup, neural crest and surface ectoderm during early gestation. Disruptions in eye morphogenesis cause severe congenital malformations, including microphthalmia (small eyes), anophthalmia (absent eyes) and coloboma (wedge-like defects in the iris and/or retina). Using high resolution SNP and meiotic linkage analysis, and related genomic methods, we have recently identified causative mutations for congenital malformations in blind humans and laboratory mice. These involve gain- and loss-of-function alleles, abnormal cell signaling, gene x gene and gene x environment interactions, and transcriptional dysregulation. Some mutant classes affect genes required for retinoid (vitamin A) biosynthesis and transport, and collectively explain a significant proportion of these heterogeneous birth defects. We are extending these observations and exploring the pathogenic mechanisms in detail.
Research Support - Principal Investigator
- NIH R01 EY019497-04 Genetic Basis of Congenital Anophthalmia. Through July 31, 2014.
- NIH R01 EY014259-07 Genetic Analysis of Retinal Ganglion Cell Function, Development and Disease. Through July 31, 2014.
1992 Glaser TM, Walton DS and RL Maas. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nature Genetics 2:232-239.
1994 Glaser TM, Jepeal L, Edwards JG, Young SR, Favor J and RL Maas. PAX6 gene dosage effect in the family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nature Genetics 7:463-471.
1998 Brown NL, Kanekar S, Vetter ML, Tucker PK, Gemza D, and T Glaser. Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of neurogenesis. Development 125:4821-4833.
2000 Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, and Glaser T. 3’ deletions cause aniridia by preventing PAX6 expression. Proc. Natl. Acad. Sci. USA 97:13755-13759.
2001 Brown NL, Patel S, Brzezinski J, and Glaser T. Math5 is required for retinal ganglion cell and optic nerve formation. Development 128:2497-2508.
2001 Tucker P, Laemle L, Munson A, Kanekar S, Oliver ER, Brown N, Schlecht H, Vetter M, and Glaser T. The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene. Genesis 31:43-53.
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2005 Brzezinski JA , Brown NL, Tanikawa A, Bush RA, Sieving PA, Vitaterna M, Takahashi J and Glaser T. Abnormal circadian behavior and retinal electrophysiology in Math5 mutant mice. Invest Ophthal Vis Sci 46:2540-2550.
2008 Saul SM, Brzezinski JA, Altshuler RM, Shore SE, Rudolph DD, Kabara LL, Halsey KE, Hufnagel RB, Dolan DF, Glaser T. Math5 expression and function in the central auditory system. Mol Cell Neurosci 37:153-169.
2010 Prasov L, Brown NL and Glaser T. A critical analysis of Atoh7 (Math5) mRNA splicing in the developing mouse retina. PLoS ONE 5(8):e12315.
2011 Ghiasvand NM, Rudolph DR, Mashayekhi M, Brzezinski JA, Goldman DJ and Glaser T. Deletion of a remote enhancer for ATOH7 disrupts neurogenesis, causing nonsyndromic congenital retinal nonattachment. Nature Neurosci 14:578-586.
2012 Brzezinski JA, Prasov L and Glaser T. Math5 defines the ganglion competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. Dev Biol 365:395-413.
2012 Prasov L, Masud T, Khaliq S, Mehdi SQ, Abid A, Oliver ER, Silva ED, Lewanda AF, Brodsky MC, Borchert M, Kelberman D, Sowden JC, Dattani MT and Glaser T. ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Hum Molec Genet 21:3681-3694.
2012 Prasov L, Nagy M, Rudolph DD and Glaser T. Math5 (Atoh7) gene dosage limits retinal ganglion cell genesis. Neuroreport 23:631-634.
2012 Prasov L and Glaser T. Pushing the envelope of retinal ganglion cell genesis: context dependent function of Math5 (Atoh7). Dev Biol 368:214-230.
2012 Prasov L and Glaser T. Dynamic expression of ganglion cell markers in retinal progenitors during the terminal cell cycle. Mol Cell Neurosci 50:160-168.