Sall1 and Sall4 cooperatively interact with Myocd and SRF to promote cardiomyocyte proliferation by regulating CDK and cyclin genes

• Published in: Development (Cambridge) Vol. 150; no. 24
• Main Authors: Katano, Wataru, Mori, Shunta, Sasaki, Shun, Tajika, Yuki, Tomita, Koichi, Takeuchi, Jun K, Koshiba-Takeuchi, Kazuko
• Format: Journal Article
• Language: English
• Published: England 15.12.2023
• Subjects: Animals; Cell Proliferation - genetics; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Cyclins - genetics; Cyclins - metabolism; Mice; Myocytes, Cardiac - metabolism; Serum Response Factor - genetics; Serum Response Factor - metabolism; Transcription Factors - metabolism; Cyclin; Myocd; Sall4; Sall1; Heart development; SRF
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.201913

Sall1 and Sall4 (Sall1/4), zinc-finger transcription factors, are expressed in the progenitors of the second heart field (SHF) and in cardiomyocytes during the early stages of mouse development. To understand the function of Sall1/4 in heart development, we generated heart-specific Sall1/4 functionally inhibited mice by forced expression of the truncated form of Sall4 (ΔSall4) in the heart. The ΔSall4-overexpression mice exhibited a hypoplastic right ventricle and outflow tract, both of which were derived from the SHF, and a thinner ventricular wall. We found that the numbers of proliferative SHF progenitors and cardiomyocytes were reduced in ΔSall4-overexpression mice. RNA-sequencing data showed that Sall1/4 act upstream of the cyclin-dependent kinase (CDK) and cyclin genes, and of key transcription factor genes for the development of compact cardiomyocytes, including myocardin (Myocd) and serum response factor (Srf). In addition, ChIP-sequencing and co-immunoprecipitation analyses revealed that Sall4 and Myocd form a transcriptional complex with SRF, and directly bind to the upstream regulatory regions of the CDK and cyclin genes (Cdk1 and Ccnb1). These results suggest that Sall1/4 are critical for the proliferation of cardiac cells via regulation of CDK and cyclin genes that interact with Myocd and SRF.