Runx1 contributes to the functional switching of bone morphogenetic protein 4 (BMP4) from neurite outgrowth promoting to suppressing in dorsal root ganglion

• Runx1 deficiency inhibited neurite outgrowth in DRG.
• Runx1 deficiency disrupted BMP4-induced neurite outgrowth inhibition in DRG.
• Runx1 deficiency enhanced CGRP expression in DRG neurons.
• Only small-sized CGRP-positive DRG neurons were increased in Runx1-deficient mice.
• CRLR-immunoreactivity was reduced in Runx1-deficient DRG neurons.

The runt-related transcription factor Runx1 regulates cell-type specification and axonal projections of nociceptive dorsal root ganglion (DRG) neurons, whereas bone morphogenetic protein 4 (BMP4) is required for axonal growth during neuronal development. Although Runx1 has been shown to be involved in BMP4 signaling in non-neural tissues, the Runx1 function in BMP4-dependent regulation of neuronal development is unclear. To investigate interactions between Runx1 and BMP4 in neurite outgrowth, we cultured DRGs from wild-type and Runx1-deficient mouse embryos in the presence or absence of BMP4. Neurite outgrowth was decreased in BMP4-treated wild-type DRGs and untreated Runx1-deficient DRGs, suggesting the inhibitory effect of BMP4 and facilitatory effect of Runx1 on neurite outgrowth. In addition, the combination of BMP4 treatment and Runx1 deficiency increased neurite outgrowth, suggesting that Runx1 is required for BMP4-induced suppression of neurite outgrowth and that the loss of Runx1 results in a functional switch of BMP4 from neurite growth suppressing to neurite growth promoting. Both BMP4 treatment and Runx1 deficiency increased calcitonin gene-related peptide (CGRP)-positive neurons, and CGRP expression was not increased by BMP4 treatment in Runx1-deficient mice, suggesting that Runx1 contributes to BMP4-induced CGRP expression in DRG neurons. Thus, Runx1 contributes to BMP4 regulation of neurite outgrowth and CGRP expression in DRG and may control BMP4 functional switching during embryogenesis.

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