title: Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5.
abstract: The pacemaker is composed of specialized cardiomyocytes located within the sinoatrial node (SAN), and is responsible for originating and regulating the heart beat. Recent advances towards understanding the SAN development have been made on the genetic control and gene interaction within this structure. Here we report that the Shox2 homeodomain transcription factor is restrictedly expressed in the sinus venosus region including the SAN and the sinus valves during embryonic heart development. Shox2 null mutation results in embryonic lethality due to cardiovascular defects, including an abnormal low heart beat rate (bradycardia) and severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation. Genetically, the lack of Tbx3 and Hcn4 expression, along with ectopic activation of Nppa, Cx40, and Nkx2-5 in the Shox2(-/-) SAN region, indicates a failure in SAN differentiation. Furthermore, Shox2 overexpression in Xenopus embryos results in extensive repression of Nkx2-5 in the developing heart, leading to a reduced cardiac field and aberrant heart formation. Reporter gene expression assays provide additional evidence for the repression of Nkx2-5 promoter activity by Shox2. Taken together our results demonstrate that Shox2 plays an essential role in the SAN and pacemaker development by controlling a genetic cascade through the repression of Nkx2-5.
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Espinoza-Lewis
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.forename: Fenglei
authors.initials: F
authors.lastname: He
authors.forename: Hongbing
authors.initials: H
authors.lastname: Liu
authors.forename: Ruhang
authors.initials: R
authors.lastname: Tang
authors.forename: Jiangli
authors.initials: J
authors.lastname: Shi
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Sun
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.forename: Dazhi
authors.initials: D
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: YiPing
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D006339:Heart Rate; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012849:Sinoatrial Node / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000033:anatomy & histology / Q000196:embryology
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; C484663:Shox2 protein, mouse; D014157:Transcription Factors