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Both environmental cues and intracellular bioenergetic states profoundly affect intraceUular pH （pHi）. How a cell responds to phi changes to maintain bioenergetic homeostasis remains elusive. Here we show that Smad5, a well-characterized downstream component of bone morphogenetic protein （BMP） signaling responds to pHi changes. Cold, basic or hypertonic conditions increase phi, which in turn dissociates protons from the charged amino acid clusters within the MH1 domain of SmadS, prompting its relocation from the nucleus to the cytoplasm. On the other hand, heat, acidic or hypotonic conditions decrease pHi, blocking the nuclear export of Smad5, and thus causing its nuclear accumulation. Active nucleocytoplasmic shuttling of Smad5 induced by environmental changes and pHi fluctuation is independent of BMP signaling, carboxyl terminus phosphorylation and Smad4. In addition, ablation of Smad5 causes chronic and irreversible dysregulation of cellular bioenergetic homeostasis and disrupted normal neural developmental processes as identified in a differentiation model of human pluripotent stem cells. Importantly, these metabolic and developmental deficits in Smad5-deficient cells could be rescued only by cytoplasmic Smad5. Cytoplasmic Smad5 physically interacts with hexokinase 1 and accelerates glycolysis. Together, our findings indicate that Smad5 acts as a pHi messenger and maintains the bioenergetic homeostasis of cells by regulating cytoplasmic metabolic machinery.

Maternal nutrition is crucial for the offspring’s skeleton development and the onset of osteoporosis later in life. While maternal low protein diet has been shown to regulate bone mass negatively, the effect of a high protein diet (HP) remains unexplored. Here, we found that C57BL/6 mice fed with HP delivered offspring with decreased skeletal mineralization at birth and reduced bone mass throughout their life due to a decline in their osteoblast maturation. A small RNA sequencing study revealed that miR-24-1-5p was highly upregulated in HP group osteoblasts. Target prediction and validation studies identified SMAD-5 as a direct target of miR-24-1-5p. Furthermore, mimic and inhibitor studies showed a negative correlation between miR-24-1-5p expression and osteoblast function. Moreover, ex vivo inhibition of miR-24-1-5p reversed the reduced maturation and SMAD-5 expression in the HP group osteoblasts. Together, we show that maternal HP diminishes the bone mass of the offspring through miR-24-1-5p.

Platelet-derived growth factors (PDGFs) play important roles in skeletal development and bone fracture healing, yet how PDGFs execute their functions remains incompletely understood. Here we show that PDGF-AA, but not -AB or -BB, could activate the BMP-Smad1/5/8 pathway in mesenchymal stem cells (MSCs), which requires BMPRIA as well as PDGFRα. PDGF-AA promotes MSC osteogenic differentiation through the BMP-Smad1/5/8-Runx2/Osx axis and MSC migration via the BMP-Smad1/5/8-Twist1/Atf4 axis. Mechanistic studies show that PDGF-AA activates BMP-Smad1/5/8 signaling by feedback down-regulating PDGFRα, which frees BMPRI and allows for BMPRI-BMPRII complex formation to activate smad1/5/8, using BMP molecules in the microenvironment. This study unravels a physical and functional interaction between PDGFRα and BMPRI, which plays an important role in MSC differentiation and migration, and establishes a link between PDGF-AA and BMPs pathways, two essential regulators of embryonic development and tissue homeostasis.

Amniotes, regardless of genetic sex, develop two sets of genital ducts: the Wolffian and Müllerian ducts. For normal sexual development to occur, one duct must differentiate into its corresponding organs, and the other must regress. In mammals, the Wolffian duct differentiates into the male reproductive tract, mainly the vasa deferentia, epididymides, and seminal vesicles, whereas the Müllerian duct develops into the four components of the female reproductive tract, the oviducts, uterus, cervix, and upper third of the vagina. In males, the fetal Leydig cells produce testosterone, which stimulates the differentiation of the Wolffian duct, whereas the Sertoli cells of the fetal testes express anti-Müllerian hormone, which activates the regression of the Müllerian duct. Anti-Müllerian hormone is a member of the transforming growth factor-beta (TGF-beta) family of secreted signaling molecules and has been shown to signal through the BMP pathway. It binds to its type II receptor, anti-Müllerian hormone receptor 2 (AMHR2), in the Müllerian duct mesenchyme and through an unknown mechanism(s); the mesenchyme induces the regression of the Müllerian duct mesoepithelium. Using tissue-specific gene inactivation with an Amhr2-Cre allele, we have determined that two TGF-beta type I receptors (Acvr1 and Bmpr1a) and all three BMP receptor-Smads (Smad1, Smad5, and Smad8) function redundantly in transducing the anti-Müllerian hormone signal required for Müllerian duct regression. Loss of these genes in the Müllerian duct mesenchyme results in male infertility due to retention of Müllerian duct derivatives in an otherwise virilized male.

Anti-Müllerian hormone (AMH) is a member of the TGF-β superfamily secreted by the gonads of both sexes. This hormone is primarily known for its role in the regression of the Müllerian ducts in male fetuses. In females, AMH is expressed in granulosa cells of developing follicles. Like other members of the TGF-β superfamily, AMH transduces its signal through two transmembrane serine/threonine kinase receptors including a well characterized type II receptor, AMHR-II. The complete signalling pathway of AMH involving Smads proteins and the type I receptor is well known in the Müllerian duct and in Sertoli and Leydig cells but not in granulosa cells. In addition, few AMH target genes have been identified in these cells. Finally, while several co-receptors have been reported for members of the TGF-β superfamily, none have been described for AMH. Here, we have shown that none of the Bone Morphogenetic Proteins (BMPs) co-receptors, Repulsive guidance molecules (RGMs), were essential for AMH signalling. We also demonstrated that the main Smad proteins used by AMH in granulosa cells were Smad 1 and Smad 5. Like for the other AMH target cells, the most important type I receptor for AMH in these cells was BMPR-IA. Finally, we have identified a new AMH target gene, Id3, which could be involved in the effects of AMH on the differentiation of granulosa cells and its other target cells.

Smad proteins are intracellular mediators of signalling initiated by Tgf-βsuperfamily ligands (Tgf-βs, activins and bone morphogenetic proteins (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific type I receptors, and associate with the common partner Smad4 to trigger transcriptional responses 1 . The inhibitory Smads (6 and 7) are transcriptionally induced in cultured cells treated with Tgf-β superfamily ligands, and downregulate signalling in in vitro assays 2 , 3 , 4 , 5 , 6 , 7 . Gene disruption in mice has begun to reveal specific developmental and physiological functions of the signal-transducing Smads. Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities. Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants. These defects highlight the importance of Smad6 in the tissue-specific modulation of Tgf-β superfamily signalling pathways in vivo .

Iodine deficiency (ID) during development results in dysfunction of the central nervous system (CNS) and affects psychomotor and motor function. It is worth noting that maternal mild and marginal ID tends to be the most common reason of preventable neurodevelopmental impairment, via a mechanism that has not been elucidated. Therefore, our aim was to study the effects of developmental mild and marginal ID on the differentiation of cerebellar granule cells (GCs) and investigate the activation of BMP-Smad1/5/8 signaling, which is crucial for the development and differentiation of cerebellum. Three developmental rat models were created by feeding dam rats with a diet deficient in iodine and deionized water supplemented with potassium iodide. Our results showed that different degrees of ID inhibited and delayed the differentiation of cerebellar GCs on postnatal day (PN) 7, PN14, and PN21. Moreover, mild and severe ID reduced the expression of BMP2 and p-Smad1/5/8, and increased the levels of Id2 on PN7, PN14, and PN21. However, marginal ID rarely altered expression of these proteins in the offspring. Our study supports the hypothesis that mild and severe ID during development inhibits the differentiation of cerebellar GCs, which may be ascribed to the down-regulation of BMP-Smad1/5/8 signaling and the overexpression of Id2. Furthermore, it was speculated that maternal marginal ID rarely affected the differentiation of cerebellar GCs in the offspring.

Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1–Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16 INK4a . c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16 INK4a upregulation and osteoblast senescence. Mouse genetic studies revealed that p16 INK4a controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16 INK4a expression and osteoprogenitor expansion. Li and colleagues report that c-Abl regulates the responses downstream of bone morphogenetic protein (BMP) that direct proliferation or senescence in osteoblasts. They show that phosphorylation of the BMP receptor BMPR1A by c-Abl promotes downstream Smad-mediated responses and osteoblast expansion, whereas in the absence of c-Abl, BMP activates Erk signalling, leading to p16 INK4a -induced senescence.