OR39-2 Persistent Notch1 and Notch2 Activity in Embryonic Pituitary Progenitor Cells Reveal Non-redundant Functions for Notch Receptors and Roles in Normal Organ Development

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR39-Pituitary
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 133 (Moscone Center)
Leonard Cheung*1, Karine Rizzoti1, Robin Lovell-Badge2 and Paul R. Le Tissier3
1Natl Inst for Medical Research, London, United Kingdom, 2National Inst for Med Rsch, London, United Kingdom, 3UCL, London, United Kingdom
The Notch signalling pathway is a conserved signal transduction pathway responding to binding of extracellular ligands to the Notch receptors. Notch pathway components are expressed during pituitary development, and are thought to regulate the progression of progenitor cells into committed endocrine cell-types. Persistent expression of Notch receptors at key stages of pituitary development inhibits the terminal differentiation of endocrine cells (1, 2). Our studies have investigated the effects of persistent Notch1 and Notch2 activity within a specific subset of embryonic progenitors during pituitary development.

Using Nkx3.1Cre/+ mice with Cre recombinase expression in a majority of pituitary precursor cells from e9.5, we have constitutively activated Notch1 and Notch2 signalling within a proportion of pituitary embryonic progenitor cells. By generating Nkx3.1Cre/+; Rosa26floxSTOP-Notch1/+ or Nkx3.1Cre/+; Rosa26floxSTOP-Notch2/+ embryos we have shown that differential phenotypes arise as a result of constitutively active signalling from the two receptors. Terminal differentiation of all hormone cell types progresses despite persistent Notch signalling, which we have confirmed using tamoxifen inducible expression of Cre in Sox9CreERT2 mice. Despite normal differentiation, overactivation of Notch1 in Nkx3.1 cells leads to inhibition of expression of Pou1f1, GH and MSH, whilst overactivation of Notch2 leads to only inhibition of MSH. It is not possible to further examine the effects in postnatal mice as Notch overactivation in non-pituitary tissues contribute to postnatal lethality. Overactivation of either Notch1 or Notch2 leads to pituitary dysmorphia, appearing to be due to an expansion of the Rathke’s cleft, although the dysmorphology differs between the two models. Analysis of canonical Notch target genes reveals a similar level of pathway activation in the two models, suggesting distinct regulation of target genes by the two receptors. These data contrast with previous studies suggesting overlapping and compensatory actions of the four mammalian Notch receptors. The differential downstream targets that are activated by specific Notch receptors can be studied through RNA sequencing of transgenic pituitaries. Our studies suggest that there are distinct differential actions of Notch receptors expressed during pituitary development, which act to temporally regulate the terminal differentiation of hormone-producing cells from embryonic pituitary progenitors.

(1) Raetzman et al. Mol Endocrinol. 2006; 20: 2898-908.  (2) Goldberg et al. Dev Biol. 2011; 358: 23-32.

Nothing to Disclose: LC, KR, RL, PRL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Medical Research Council, UK, file reference number U117562207.