title: Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics.
abstract: Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumor-transforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing.
authors.affiliation: Neuroscience Research Institute,Department of Molecular, Cellular, Developmental Biology, and.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Keeley
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN 38120; andJiangsu Key Laboratory of Neuroregenertion, Nantong University, Nantong 226001, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN 38120; and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
authors.affiliation: Neuroscience Research Institute,Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA 93106; breese@psych.ucsb.edu.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Reese
mesh_terms: D025042:Amacrine Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D059329:Cholinergic Neurons / Q000166:cytology / Q000378:metabolism*; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D064249:Securin / Q000096:biosynthesis* / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D005136:Eye Proteins; C578005:PTTG1 protein, mouse; D064249:Securin
keywords: nearest neighbor distance; quantitative trait locus; recombinant inbred mice; regularity index