Regulation of the Pax6 : Pax6(5a) mRNA ratio in the developing mammalian brain

Jeni Pinson,T Ian Simpson,John O Mason,David J Price

doi:10.1186/1471-213x-5-13

Abstract

BackgroundEarly in mammalian brain development cell proliferation generates a population of progenitor cells whose subsequent divisions produce increasing numbers of postmitotic neurons. Pax6 affects both processes and it has been suggested that this changing role is due at least in part to changes in the relative concentrations of its two main isoforms, (i) Pax6 and (ii) Pax6(5a), created by insertion of a 42 bp exon (exon 5a) into one of the two DNA-binding domains. Crucially, however, no previous study has determined whether the ratio between Pax6 and Pax6(5a) transcripts alters during mammalian neurogenesis in vivo.ResultsUsing RNase protection assays, we show that Pax6 transcripts are 6–10 times more prevalent than Pax6(5a) transcripts early in neurogenesis in the murine telencephalon, diencephalon and hindbrain and that the ratio later falls significantly to about 3:1 in these regions.ConclusionThese changes in vivo are similar in magnitude to those shown previously to alter target gene activity in vitro and might, therefore, allow the single mammalian Pax6 gene to carry out different functions at different times in mammalian brain development.

Highlights

In mammalian brain development cell proliferation generates a population of progenitor cells whose subsequent divisions produce increasing numbers of postmitotic neurons
Pax6 is expressed in the developing eye and brain, where it affects both progenitor cell production and neuronal differentiation [1-5]
The paired domain (PD) consists of two separate helix-turn-helix motifs, termed PAI and RED, which act on different target sequences [6]

Summary

Introduction

In mammalian brain development cell proliferation generates a population of progenitor cells whose subsequent divisions produce increasing numbers of postmitotic neurons. The best characterised Pax alternative splicing event, involving the insertion of a 42 bp exon (exon 5a) into the PAI subdomain of the PD, results in two major Pax isoforms [Pax and Pax6(5a)] with different DNA-binding properties. Pax affects early progenitor cell proliferation and later neuronal differentiation in the developing brain [4,5]. This changing role might be due at least in part to a shift in the relative concentrations of Pax and Pax6(5a) during development but there has been no previous report of such alterations during neurogenesis in the brain in vivo. We anticipated that even relatively small changes in the Pax : Pax6(5a) ratio might be important since stronger effects on gene activity via P6CON and 5aCON are observed if Pax and Pax6(5a) are introduced into (page number not for citation purposes)

Methods

Results

Conclusion