title: Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse.
abstract: Hoxa3 was the first Hox gene to be mutated by gene targeting in mice and is required for the development of multiple endoderm and neural crest cell (NCC)-derived structures in the pharyngeal region. Previous studies have shown that the Hoxa3 null mutant lacks third pharyngeal pouch derivatives, the thymus and parathyroids by E18.5, and organ-specific markers are absent or downregulated during initial organogenesis. Our current analysis of the Hoxa3 null mutant shows that organ-specific domains did undergo initial patterning, but the location and timing of key regional markers within the pouch, including Tbx1, Bmp4 and Fgf8, were altered. Expression of the parathyroid marker Gcm2 was initiated but was quickly downregulated and differentiation failed; by contrast, thymus markers were delayed but achieved normal levels, concurrent with complete loss through apoptosis. To determine the cell type-specific roles of Hoxa3 in third pharyngeal pouch development, we analyzed tissue-specific mutants using endoderm and/or NCC-specific Cre drivers. Simultaneous deletion with both drivers resulted in athymia at E18.5, similar to the null. By contrast, the individual tissue-specific Hoxa3 deletions resulted in small, ectopic thymi, although each had a unique phenotype. Hoxa3 was primarily required in NCCs for morphogenesis. In endoderm, Hoxa3 temporally regulated initiation of the thymus program and was required in a cell-autonomous manner for parathyroid differentiation. Furthermore, Hoxa3 was required for survival of third pharyngeal pouch-derived organs, but expression in either tissue was sufficient for this function. These data show that Hoxa3 has multiple complex and tissue-specific functions during patterning, differentiation and morphogenesis of the thymus and parathyroids.
authors.affiliation: Department of Genetics, Paul D. Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA.
authors.forename: Jena L
authors.initials: JL
authors.lastname: Chojnowski
authors.affiliation: Department of Genetics, Paul D. Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Genetics, Paul D. Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA.
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Trau
authors.affiliation: Division of Hematology and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Department of Human Genetics, Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Capecchi
authors.affiliation: Department of Genetics, Paul D. Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA nmanley@uga.edu.
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Manley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism*; D001934:Branchial Region / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006652:Histological Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007211:Indoles; D051379:Mice; D008953:Models, Anatomic; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D010280:Parathyroid Glands / Q000196:embryology*; D018709:Statistics, Nonparametric; D013950:Thymus Gland / Q000196:embryology*
chemical_list: D015415:Biomarkers; D017931:DNA Primers; D005697:Galactosides; D018398:Homeodomain Proteins; C080331:Hoxa3 protein, mouse; D007211:Indoles; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: Hoxa3; Mouse; Parathyroid; Thymus