Enforced Expression of Tbx1 In Fetal Thymic Epithelial Cells Antagonizes Thymus Organogenesis

<p><strong>Enforced expression of <em>Tbx1</em> in fetal thymic epithelial cells antagonizes</strong></p> <p><strong>thymus organogenesis</strong></p> <p>Kim T. Cardenas</p> <p>The thymus and parathyroid glands originate from organ-specific domains of 3rd pharyngeal pouch (PP) endoderm. At embryonic day 11.5 (E11.5), the ventral thymus and dorsal parathyroid domains can be identified by <em>Foxn1</em> and <em>Gcm2</em> expression respectively. Neural crest cells, (NCCs) play a role in regulating patterning of 3rd PP endoderm. In addition, pharyngeal endoderm influences fate determination via secretion of Sonic hedgehog (Shh), a morphogen required for <em>Gcm2</em> expression and generation of the parathyroid domain. <em>Gcm2</em> is a downstream target of the transcription factor Tbx1, which in turn is positively regulated by Shh. Although initially expressed throughout pharyngeal pouch endoderm, <em>Tbx1</em> expression is excluded from the thymus-specific domain of the 3rd PP by E10.5, but persists in the parathyroid domain. Based on these observations, we hypothesized that <em>Tbx1</em> expression is non-permissive for thymus fate specification and that enforced expression of <em>Tbx1</em> in the fetal thymus would impair thymus development.</p> <p>To test this hypothesis, we generated knock-in mice containing a Cre-inducible allele that allows for tissue-specific <em>Tbx1</em> expression. Expression of the <em>R26^iTbx1</em> allele in fetal and adult thymus using <em>Foxn1^Cre </em>resulted in severe thymus hypoplasia throughout ontogeny that persisted in the adult. Thymic epithelial cell (TEC) development was impaired as determined by immunohistochemical and FACS analysis of various differentiation markers. The relative level of <em>Foxn1 </em>expression in fetal TECs was significantly reduced. TECs in <em>R26^iTbx1/+</em> thymi assumed an almost universal expression of Plet-1, a marker associated with a TEC stem/progenitor cell fate. In addition, embryonic <em>R26^iTbx1/+</em> mice develop a perithymic mesechymal capsule that appears expanded compared to control littermates. Interestingly, thymi from neonatal and adult <em>R26^iTbx1/+</em> but not <em>R26^+/+</em> mice were encased in adipose tissue. This thymic phenotype also correlated with a decrease in thymocyte cellularity and aberrant thymocyte differentiation. The results to date support the conclusion that enforced expression of <em>Tbx1</em> in TECs antagonizes their differentiation and prevents normal organogenesis via both direct and indirect effects.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Cardenas, Kim T

Contributors dc:contributor

• Ellen Richie
• Mark Bedford
• David Johnson

• thymus
• thymus organogenesis
• 3rd pharyngeal pouch
• Tbx1
• thymic epithelial
• thymic development
• Cancer Biology
• Cell and Developmental Biology
• Cell Biology
• Developmental Biology
• Genetic Processes
• Immunity
• Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/157

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1183