The pituitary gland is a very convenient model to study mechanisms implicated in cellular differentiation. This endocrine gland is composed of six cell lineages, each committed to the production of a different hormone: thyrotrophs (TSH), somatotrophs (GH), lactotrophs (PRL), gonadotrops (LH, FSH), melanotrophs (alpha-MSH) and corticotrophs (ACTH). ACTH and alpha-MSH are both processed from the same precursor, proopiomelanocortin (POMC). Pituitary hormone-producing cells differentiate sequentially from a common epithelial primordium, Rathke's pouch, under the combinatorial action of a subset of tissue- and cell-restricted transcription factors. In corticotrophs, Tpit and NeuroD1 are important for POMC transcription. Their expression closely precedes that of POMC, suggesting a role in the differentiation of this lineage. In order to better define the role of Tpit in POMC cell differentiation, we generated Tpit-null mice. These mice are deficient in POMC-expressing cells while other pituitary lineages are normal. Analysis of other corticotroph markers, such as NeuroD1, showed that lineage commitment was preserved in absence of Tpit. We next tested if Tpit and -NeuroD1 could be jointly required for corticotroph determination by producing Tpit-/- NeuroD1-/- mice. This experiment revealed that these two factors are not essential for early determination of corticotroph cells, suggesting different levels of control for commitment of POMC lineages compared to cell survival or to cell-specific transcription of POMC. Further investigation of Tpit-/- mice has revealed that Tpit is a negative regulator of the gonadotroph fate. These studies suggest a binary model of cell fate decisions for pituitary cell differentiation, suggesting the presence of a pituitary pluripotent precursor. Finally we have shown that mutations in the coding sequence of human TPIT are associated with isolated ACTH deficiency, a pathology very similar to that found in Tpit-null m
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85638 |
| Date | January 2005 |
| Creators | Pulichino, Anne-Marie |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | French |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002207423, proquestno: AAINR12930, Theses scanned by UMI/ProQuest. |
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