YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP’s function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice. This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.

Highlights d Cul3 mutant mice exhibits social behavioral deficits and anxiety-like behaviors d CUL3 deficiency impairs neurotransmission, excitability, and E-I balance d Protein translation and synaptic vesicle turnover are increased in Cul3 mutant mice d Inhibiting protein translation rescues social behavior and neurotransmission deficits

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Neurogenesis is thought to play a role in cognitive function and hippocampal plasticity. Previous studies suggest that neurogenesis declines with aging. However, the onset and mechanism of declined neurogenesis are not fully elucidated. Here we show that the major decline in neurogenesis takes place during adulthood, prior to aging. Decline in neurogenesis takes place in both the subgranular layer of the dentate gyrus and in the subventricular zone, and is primarily due to reduced number of fast-proliferating neural progenitor cells. Importantly, this decline can be rescued by intraventricular injection of recombinant soluble amyloid precursor protein (sAPPα) that regulates neural progenitor cell proliferation in the adult brain. The counterpart sAPPβ, a product of the amyloidogenic cleavage pathway of APP, fails to exhibit a proliferative effect in vitro and in vivo, in equimolar concentration to sAPPα. These observations suggest that adulthood is an appropriate time window for an intervention that upregulates neurogenesis, such as enhancement of sAPPα levels, for the prevention of declining brain plasticity and cognitive function.

Yes-associated protein (Yap) is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. In this study, we characterized Yap's role in the formation of the neuromuscular junction (NMJ). In HSA-Yap Ϫ/Ϫ mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and were distributed in a broader region in the middle of muscle fibers, suggesting that muscle Yap is necessary for the size and location of AChR clusters. In addition, HSA-Yap Ϫ/Ϫ mice also exhibited remarkable presynaptic deficits. Many AChR clusters were not or less covered by nerve terminals; miniature endplate potential frequency was reduced, which was associated with an increase in paired-pulse facilitation, indicating structural and functional defects. In addition, muscle Yap mutation prevented reinnervation of denervated muscle fibers. Together, these observations indicate a role of muscle Yap in NMJ formation and regeneration. We found that ␤-catenin was reduced in the cytoplasm and nucleus of mutant muscles, suggesting compromised ␤-catenin signaling. Both NMJ formation and regeneration deficits of HSA-Yap Ϫ/Ϫ mice were ameliorated by inhibiting ␤-catenin degradation, further corroborating a role of ␤-catenin or Wnt-dependent signaling downstream of Yap to regulate NMJ formation and regeneration.

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ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression.ErbB2 | Erbin | HSP90 | breast cancer | stability T he human epidermal growth factor receptor (HER) family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR, HER1, ErbB1), ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; HER2, neu), ErbB3 (HER3), and ErbB4 (HER4), has been implicated in tumor growth and progression. ErbB2, in particular, is overexpressed in around 25% of breast cancers, conferring high recurrence, malignant metastasis, and poor prognosis, (1, 2) and is also overexpressed in ovarian, stomach, and uterine tumors (3, 4). Upon ligand stimulation, ErbB receptors dimerize to activate downstream signaling (4). Unique in the ErbB family, ErbB2 does not have a ligand but is a preferred heterodimerization partner of other ErbB receptors in response to ligand stimulation. In mice, overexpression of ErbB2 or its activated form in mammary epithelium induces diffuse epithelial hyperplasia, mammary tumors, and lung metastases (5, 6). Unlike other ErbB members such as EGFR, which, upon activation, becomes internalized and sorted to lysosomes for degradation, ErbB2 is refractory to endocytosis and degradation (7,8). The underlying mechanisms of ErbB2 stability are not well characterized.Erbin is a cytoplasmic protein that contains leucine-rich repeats (LRR) and PSD95/Dlg1/zo-1 (PDZ) domain (thus named a LAP protein) (9, 10). Erbin interacts, via its single PDZ domain, specifically with ErbB2, but not with ErbB3, ErbB4, or EGFR (11,12). It is colocalized with ErbB2 at the basolateral membranes of epithelial cells (11). In vitro studies are inconsistent regarding the role of Erbin in cell proliferation and tumorigenesis. It was thought to act as a tumor suppressor by inhibiting TGFβ or Erk signaling (13-15). On the other hand, knockdown of Erbin in HT-29 colon cancer cells appears to inhibit the formation of multicellular tumor spheroids (16).Here we report that Erbin is exp...