The Rho guanine nucleotide exchange factor AKAP13 (BRX) is essential for cardiac development in mice.
A fundamental biologic principle is that diverse biologic signals are channeled through shared signaling cascades to regulate development. Large scaffold proteins that bind multiple proteins are capable of coordinating shared signaling pathways to provide specificity to activation of key developmental genes. Although much is known about transcription factors and target genes that regulate cardiomyocyte differentiation, less is known about scaffold proteins that couple signals at the cell surface to differentiation factors in developing heart cells. Here we show that AKAP13 (also known as Brx-1, AKAP-Lbc, and proto-Lbc), a unique protein kinase A-anchoring protein (AKAP) guanine nucleotide exchange region belonging to the Dbl family of oncogenes, is essential for cardiac development. Cardiomyocytes of Akap13-null mice had deficient sarcomere formation, and developing hearts were thin-walled and mice died at embryonic day 10.5-11.0. Disruption of Akap13 was accompanied by reduced expression of Mef2C. Consistent with a role of AKAP13 upstream of MEF2C, Akap13 siRNA led to a reduction in Mef2C mRNA, and overexpression of AKAP13 augmented MEF2C-dependent reporter activity. The results suggest that AKAP13 coordinates Galpha(12) and Rho signaling to an essential transcription program in developing cardiomyocytes.
Program in Reproductive and Adult Endocrinology, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chantal M
CM
Mayers
Jennifer
J
Wadell
Kate
K
McLean
Monica
M
Venere
Minnie
M
Malik
Takahisa
T
Shibata
Paul H
PH
Driggers
Tomoshige
T
Kino
X Catherine
XC
Guo
Hisashi
H
Koide
Marat
M
Gorivodsky
Alex
A
Grinberg
Mahua
M
Mukhopadhyay
Mones
M
Abu-Asab
Heiner
H
Westphal
James H
JH
Segars
D054758:A Kinase Anchor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D015778:Minor Histocompatibility Antigens; D008955:Models, Cardiovascular; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C526201:Akap13 protein, mouse; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D015778:Minor Histocompatibility Antigens; D018006:Myogenic Regulatory Factors; D034741:RNA, Small Interfering; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020741:rho GTP-Binding Proteins