Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106.
PNAS 113(31):E4494 (2016)
Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasti...
Myocardin-related transcription factors are required for skeletal muscle development.
Development 143(15):2853 (2016)
Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics. Stimuli that promote actin polymerization allow for shuttling of MRTFs to the nucleus where they activate serum response factor (SRF), a regulator of actin and oth...
Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury.
Nature 534(7605):119 (2016)
Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity. Reactivating primitive reparative ability in the mature mammalian heart ...
Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
The American Journal of Human Genetics 98(6):1082 (2016)
Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PR...
Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development.
Cell Reports 15(7):1384 (2016)
Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells, and endothelium. Hippo signaling ...
Muscle RING-finger 2 and 3 maintain striated-muscle structure and function.
Journal of Cachexia Sarcopenia and Muscle 7(2):165 (2016)
The Muscle-specific RING-finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with notic...
Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication.
Cell 164(6):1248 (2016)
Most physiological functions originate with the communication between organs. Mouse genetics has revived this holistic view of physiology through the identification of inter-organ communications that are unanticipated, functionally important, and would have been difficult to uncover otherwise. T...
Structure-function analysis of myomaker domains required for myoblast fusion.
PNAS 113(8):2116 (2016)
During skeletal muscle development, myoblasts fuse to form multinucleated myofibers. Myomaker [Transmembrane protein 8c (TMEM8c)] is a muscle-specific protein that is essential for myoblast fusion and sufficient to promote fusion of fibroblasts with muscle cells; however, the structure and bioch...
A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.
Genes & Development 30(4):434 (2016)
The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit ...
Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch.
Developmental Cell 36(3):316 (2016)
Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here, we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 express...
Yap and Taz play a crucial role in neural crest-derived craniofacial development.
Development 143(3):504 (2016)
The role of the Hippo signaling pathway in cranial neural crest (CNC) development is poorly understood. We used the Wnt1(Cre) and Wnt1(Cre2SOR) drivers to conditionally ablate both Yap and Taz in the CNC of mice. When using either Cre driver, Yap and Taz deficiency in the CNC resulted in enlarge...
Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy.
Science 351(6271):400 (2016)
CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associa...
A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle.
Science 351(6270):271 (2016)
Muscle contraction depends on release of Ca(2+) from the sarcoplasmic reticulum (SR) and reuptake by the Ca(2+)adenosine triphosphatase SERCA. We discovered a putative muscle-specific long noncoding RNA that encodes a peptide of 34 amino acids and that we named dwarf open reading frame (DWORF). ...
A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9.
PNAS 113(2):338 (2016)
Clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)9 genomic editing has revolutionized the generation of mutant animals by simplifying the creation of null alleles in virtually any organism. However, most current approaches with this method require zygote injecti...
Hypothalamic leptin action is mediated by histone deacetylase 5.
Nature Communications 7:10782 (2016)
Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake an...
LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development.
Nature Communications 7:11961 (2016)
The Hippo pathway regulates the self-renewal and differentiation of various adult stem cells, but its role in cell fate determination and differentiation during liver development remains unclear. Here we report that the Hippo pathway controls liver cell lineage specification and proliferation se...
Overexpression and knockout of miR-126 both promote leukemogenesis.
Blood 126(17):2005 (2015)
It is generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the ...
Myocardin-related transcription factors are required for cardiac development and function.
Developmental Biology 406(2):109 (2015)
Myocardin-Related Transcription Factors A and B (MRTF-A and MRTF-B) are highly homologous proteins that function as powerful coactivators of serum response factor (SRF), a ubiquitously expressed transcription factor essential for cardiac development. The SRF/MRTF complex binds to CArG boxes foun...
C-terminal variable AGES domain of Thymosin β4: the molecule's primary contribution in support of post-ischemic cardiac function and repair.
Journal of Molecular and Cellular Cardiology 87:113 (2015)
Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered that Thymosin β4 (TB4), a 43 amino-a...
Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes.
PNAS 112(38):11864 (2015)
Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardi...