Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9295-300. doi: 10.1073/pnas.1323543111. Epub 2014 Jun 10.

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

Author information

1
Neuroscience Research Institute,Department of Molecular, Cellular, Developmental Biology, and.
2
Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
3
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN 38120; andJiangsu Key Laboratory of Neuroregenertion, Nantong University, Nantong 226001, China.
4
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN 38120; and.
5
Neuroscience Research Institute,Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA 93106; breese@psych.ucsb.edu.

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.

KEYWORDS:

nearest neighbor distance; quantitative trait locus; recombinant inbred mice; regularity index

PMID:
24927528
PMCID:
PMC4078852
DOI:
10.1073/pnas.1323543111
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center