Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Patrick W. Keeley, Cuiqi Zhou, Lu Lu, Robert Williams, Shlomo Melmed, Benjamin E. Reese

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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.

Original languageEnglish (US)
Pages (from-to)9295-9300
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
StatePublished - Jun 24 2014

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Pituitary Neoplasms
Oncogenes
Amacrine Cells
Inbred C57BL Mouse
Cholinergic Agents
Retinal Neurons
Chromosomes, Human, Pair 11
Transcription Factor AP-1
Interneurons
Computational Biology
Nucleotides
Chromosomes
Gene Expression
Neurons
Genes

All Science Journal Classification (ASJC) codes

  • General

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Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics. / Keeley, Patrick W.; Zhou, Cuiqi; Lu, Lu; Williams, Robert; Melmed, Shlomo; Reese, Benjamin E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 25, 24.06.2014, p. 9295-9300.

Research output: Contribution to journalArticle

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