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

Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9295-300. doi: 10.1073/pnas.1323543111. Epub 2014 Jun 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amacrine Cells / cytology
  • Amacrine Cells / metabolism*
  • Animals
  • Base Sequence
  • Cholinergic Neurons / cytology
  • Cholinergic Neurons / metabolism*
  • Eye Proteins / biosynthesis*
  • Eye Proteins / genetics
  • Gene Expression Regulation / physiology*
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Securin / biosynthesis*
  • Securin / genetics
  • Sequence Deletion


  • Eye Proteins
  • PTTG1 protein, mouse
  • Securin

Associated data

  • PDB/GN207
  • PDB/GN210
  • PDB/GN302