Abstract 44: Interaction Of Osr1 And Tbx5 Is Involved In The Mouse Limb And Heart Development

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Mutations of TBX5 cause Holt-Oram syndrome (HOS) in human, a disease characterized by upper limb and heart defects. Mouse embryos of Osr1 knockout caused similar heart defects, while the upper limb defects have never been reported. By genetically marking Osr1expressing cells in mice, using Osr1:CreERT2, we showed that Osr1 expression cells contribute to the atrial septum progenitors between E8.0 and E11.0, and to the forelimb after E9.0. The expression of Osr1 in the forelimb showed a gradient decreasing pattern from the digit 5 to digit 1. Conditional-Tbx5 haploinsuffiency, using Osr1:CreERT2, compound with Osr1 haploinsuffiency induced more incidence of atrial septal defects (ASDs) and double outlet right ventricle (DORV). Forty percent of these embryos also had digit defects: the digits are either missing, fused or lack normal identity, which were not observed in mouse embryos of either Osr1 or Tbx5 haploinsuffiency. Detailed study of the cardiac progenitors of the compound haploinsufficinecy for Tbx5 and Osr1 showed decreased proliferation in the posterior second heart field, which was associated with lower number of cells transiting from G2 to M phase and less gene expression of Cdk6 and CyclinD2. In summary, our study demonstrated that interaction of Osr1 and Tbx5 is involved in the mouse limb and heart development and provides a potential mechanism for HOS.

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