title: Nkx2-5 mediates differential cardiac differentiation through interaction with Hoxa10.
abstract: The regulation of cardiac differentiation is complex and incompletely understood. Recent studies have documented that Nkx2-5-positive cells are not limited to the cardiac lineage, but can give rise to endothelial and smooth muscle lineages. Other work has elucidated that, in addition to promoting cardiac development, Nkx2-5 plays a larger role in mesodermal patterning although the transcriptional networks that govern this developmental patterning are undefined. By profiling early Nkx2-5-positive progenitor cells, we discovered that the progenitor pools of the bisected cardiac crescent are differentiating asynchronously. This asymmetry requires Nkx2-5 as it is lost in the Nkx2-5 mutant. Surprisingly, the posterior Hox genes Hoxa9 and Hoxa10 were expressed on the right side of the cardiac crescent, independently of Nkx2-5. We describe a novel, transient, and asymmetric cardiac-specific expression pattern of the posterior Hox genes, Hoxa9 and Hoxa10, and utilize the embryonic stem cell/embryoid body (ES/EB) model system to illustrate that Hoxa10 impairs cardiac differentiation. We suggest a model whereby Hoxa10 cooperates with Nkx2-5 to regulate the timing of cardiac mesoderm differentiation.
authors.affiliation: Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Ann N
authors.initials: AN
authors.lastname: Behrens
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lohr
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Claudia
authors.initials: C
authors.lastname: Zierold
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garry
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Martin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000502:physiology*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006321:Heart / Q000196:embryology; D000080905:Homeobox A10 Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000080905:Homeobox A10 Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C092119:Hoxa10 protein, mouse