LIM homeobox transcription factor Lhx2 inhibits skeletal muscle differentiation in part via transcriptional activation of Msx1 and Msx2

Yusaku Kodaka, Kiyoko Tanaka, Kenji Kitajima, Kosuke Tanegashima, Ryoichi Matsuda, Takahiko Hara

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


LIM homeobox transcription factor Lhx2 is known to be an important regulator of neuronal development, homeostasis of hair follicle stem cells, and self-renewal of hematopoietic stem cells; however, its function in skeletal muscle development is poorly understood. In this study, we found that overexpression of Lhx2 completely inhibits the myotube-forming capacity of C2C12 cells and primary myoblasts. The muscle dedifferentiation factors Msx1 and Msx2 were strongly induced by the Lhx2 overexpression. Short interfering RNA-mediated knockdown of Lhx2 in the developing limb buds of mouse embryos resulted in a reduction in Msx1 and Msx2 mRNA levels, suggesting that they are downstream target genes of Lhx2. We found two Lhx2 consensus-binding sites in the -2097 to -1189 genomic region of Msx1 and two additional sites in the -536 to +73 genomic region of Msx2. These sequences were shown by luciferase reporter assay to be essential for Lhx2-mediated transcriptional activation. Moreover, electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that Lhx2 is present in chromatin DNA complexes bound to the enhancer regions of the Msx1 and Msx2 genes. These data demonstrate that Msx1 and Msx2 are direct transcriptional targets of Lhx2. In addition, overexpression of Lhx2 significantly enhanced the mRNA levels of bone morphogenetic protein 4 and transforming growth factor beta family genes. We propose that Lhx2 is involved in the early stage of skeletal muscle development by inducing multiple differentiation inhibitory factors.

Original languageEnglish (US)
Pages (from-to)309-319
Number of pages11
JournalExperimental Cell Research
Issue number2
StatePublished - Feb 15 2015

Bibliographical note

Funding Information:
This work was supported in part by JSPS KAKENHI ( 23390256 to T.H.) and Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP (26-8 to R.M). The anti-myogenin and anti-MyHC antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, Iowa.

Publisher Copyright:
© 2014 Elsevier Inc.


  • Lhx2
  • Limb bud
  • Msx1
  • Msx2
  • Skeletal muscle differentiation


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