Acute myeloid leukemia-associated Mkl1 (Mrtf-a) is a key regulator of mammary gland function.
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.
Sun
Yi
Y
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Boyd
Kelli
K
Xu
Wu
W
Ma
Jing
J
Jackson
Carl W
CW
Fu
Amina
A
Shillingford
Jonathan M
JM
Robinson
Gertraud W
GW
Hennighausen
Lothar
L
Hitzler
Johann K
JK
Ma
Zhigui
Z
Morris
Stephan W
SW
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002648:Child; D005183:Failure to Thrive; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D006801:Humans; D007223:Infant; D007774:Lactation / Q000502:physiology*; D007947:Leukemia, Megakaryoblastic, Acute; D008297:Male; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000033:anatomy & histology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008892:Milk; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D010121:Oxytocin / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D050796:STAT3 Transcription Factor; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C511173:Mrtfa protein, mouse; D050796:STAT3 Transcription Factor; D026362:Serum Response Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D010121:Oxytocin; D011388:Prolactin