Defining The Molecular Networks Necessary For Thymus Fate and Organogenesis

<p>The thymus and parathyroid (PT) glands originate from endodermal progenitors in the bilateral third pharyngeal pouches (3^rd pps). By E11.5 during mouse development, cells committed to the thymus lineage express <em>Foxn1 </em>whereas PT-fated cells express <em>Gcm2</em>. While these transcription factors are required for organ-specific differentiation, the exact molecular mechanisms that specify endodermal progenitors to either the thymus or parathyroid lineage are not well defined. <em>Tbx1</em> is initially expressed throughout the 3^rd pp endoderm, as it is required for segmentation of the pharyngeal apparatus, but is downregulated in the thymus-fated domain by E10.5. Despite the widely held notion that <em>Tbx1 </em>is required for thymus organogenesis, we have shown that ectopic expression of <em>Tbx1 </em>in thymic epithelial cells (TECs) suppresses FOXN1, inhibits TEC proliferation and arrests TEC differentiation, suggesting <em>Tbx1</em> must be tightly regulated in the 3^rd pp endoderm for proper thymus organogenesis to occur. Members of the <em>miR-17-92 </em>cluster downregulate <em>Tbx1 </em>in cardiac progenitor cells to permit cardiomyocyte differentiation, and we demonstrated that members of this cluster are expressed in the 3^rd pp endoderm and mesenchyme. We find that global or TEC-specific deletion of <em>miR-17-92 </em>enhances TBX1 expression and reduces FOXN1 in the 3^rd pp. Furthermore, global deletion of <em>miR-17-92 </em>results in an ectopic, hypoplastic thymus lobe, while deletion in TECs results in TBX1⁺ progenitor cells that persist in the fetal thymus. In contrast, overexpression of <em>miR-17-92 </em>in TECs results in downregulation of TBX1 in the dorsal 3^rd pp and surrounding mesenchyme. Therefore, these data suggest that <em>miR-17-92</em> plays an essential role in thymus development by regulating <em>Tbx1</em> expression in the 3^rd pp.</p> <p>Additionally, previous work from our lab has shown that a genetic deficiency in neural crest cells (NCCs) expands thymus fate in the 3^rd pp. We show that NCCs mediate this effect in part by promoting TBX1 expression in the dorsal 3^rd pp. Finally, we present evidence consistent with the dual hypothesis that <em>Fgf8</em> expression in the ventral 3^rd pp promotes thymus fate by restricting TBX1. Based on these results, we generated a working model describing the signaling networks that contribute to thymus fate and 3^rd pp patterning.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Reeh, Kaitlin A

Contributors dc:contributor

• Ellen R. Richie, PhD
• Sharon Y. R. Dent, PhD
• Richard D. Wood

• Thymus
• Tbx1
• Foxn1
• miR-17-92
• Developmental Biology
• Medicine and Health Sciences
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/635

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1670