Acute Myeloid Leukemia-Associated Mkl1 (Mrtf-a) Is a Key Regulator of Mammary Gland Function

Abstract

Transcription of immediate-early genes-as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis-is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted.Megakaryoblastic leukemia 1 (MKL1) was initially identified in acute megakaryoblastic leukemias (AMKLs) that occur in infants and young children due to its involvement in the RBM15-MKL1 fusion protein created by the t(1;22) chromosomal translocation found uniquely in these leukemias (41, 48). As a result of this translocation, the MKL1 gene (alternatively known as MAL [megakaryocytic acute leukemia], MRTF-A

Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation

“…Together, these data revealed that MKL1 functions as a gatekeeper that controls adipocyte differentiation both in vitro and in vivo. It was previously reported that the postpartum mammary glands of Mkl1 knockout female mouse show premature involution and markedly increased white adipose tissue 34 . This phenotype of Mkl1 knockout mouse is concordant with our finding that loss of Mkl1 promotes adipocyte differentiation programme.…”

Myocardin‐related transcription factor B is required for normal mouse vascular development and smooth muscle gene expression

“…Recently, it was demonstrated that MRTF-A is required for proper differentiation of mammary myoepithelial cells (Li et al, 2006;Sun et al, 2006). Homozygous MRTF-A mutant mothers are unable to nurse their offspring due to a defect in differentiation of mammary myoepithelial cell, a smooth muscle-like cell type required for milk ejection.…”

“…MRTF-A (also called Mkl1/MAL/ BSAC) and MRTF-B (also referred to as Mkl2/MAL16) can also promote SRF-dependent transcription in response to intracellular cytoskeletal changes by translocating to the nucleus in response to Rho GTPase and actin signaling (Miralles et al, 2003;Du et al, 2004;Kuwahara et al, 2005). Recently, it was shown that MRTF-A null mice are unable to nurse their young due to a defect in myoepithelial cells important for lactation (Li et al, 2006;Sun et al, 2006). The phenotype of the MRTF-A null mice is quite restricted despite the broad expression of MRTF-A in multiple tissues.…”

The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development

“…1,2 The human MAL gene is fused to the OTT/ RBM15 gene in acute megakaryoblastic leukemia (AMKL) 3,4 and a contribution of Mal activity to the late steps of murine and human megakaryopoiesis has been reported. 5,6 Although the lack of Srf results in major cellular defects and embryonic lethality (reviewed in Miano et al 7 ), Mal germ line deficiency results in a limited myoepithelial cells phenotype 8,9 probably because of the redundancies of Mrtf proteins.…”