The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.

New developments in the biology of fibroblast growth factors.

BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.

/pdf/bmp-signaling-pathway-in-dentin-development-and-diseases-1o3zc83n.pdf

BMP Signaling Pathway in Dentin Development and Diseases

Recurrent miscarriage (RM) affects 1%-3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene [B(a)P], a representative of polycyclic aromatic hydrocarbons (PAHs), is correlated with miscarriage. However, the underlying mechanisms of B(a)P/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-induced trophoblast cell dysfunctions and miscarriage remain largely unknown.The objective was to discover the role(s) of a novel lncRNA, lnc-HZ09, in the regulation of BPDE-inhibited migration and invasion of trophoblast cells and the occurrence of miscarriage.Human trophoblast cells were treated with 0, 0.25, 0.5, 1.0, or 1.5μM BPDE with or without corresponding lnc-HZ09 silencing or overexpression. Using these cells, we evaluated cell migration and invasion, the mRNA and protein levels of members of the PLD1/RAC1/CDC42 pathway, the regulatory roles of lnc-HZ09 in PLD1 transcription and mRNA stability, and lnc-HZ09 transcription and stability. Human villous tissues were collected from RM (n=15) group and their matched healthy control (HC, n=15) group. We evaluated the levels of BPDE-DNA adducts, lnc-HZ09, and the mRNA and protein expression of members of the PLD1/RAC1/CDC42 pathway, and correlated their relative expression levels. We further constructed 0, 0.05 or 0.2mg/kg B(a)P-induced mouse miscarriage model (each n=6), in which the mRNA and protein expression of members of the Pld1/Rac1/Cdc42 pathway were measured.We identified a novel lnc-HZ09. Human trophoblast cells treated with lnc-HZ09 exhibited less cell migration and invasion. In addition, the levels of this lncRNA were higher in villous tissues from women with recurrent miscarriage than those from healthy individuals. SP1-mediated PLD1 mRNA levels were lower, and HuR-mediated PLD1 mRNA stability was less in trophoblast cells overexpressing lnc-HZ09. However, trophoblast cells treated with MSX1 had higher levels of lnc-HZ09, and METTL3-mediated m6A methylation on lnc-HZ09 resulted in greater lnc-HZ09 RNA stability. In BPDE-treated human trophoblast cells and in RM villous tissues, MSX1-mediated lnc-HZ09 transcription and METTL3-mediated lnc-HZ09 stability were both greater. In our mouse miscarriage model, B(a)P-treated mice had lower mRNA and protein levels of members of the Pld1/Rac1/Cdc42 pathway.These results suggest that in human trophoblast cells, BPDE exposure up-regulated lnc-HZ09 level, suppressed PLD1/RAC1/CDC42 pathway, and inhibited migration and invasion, providing new insights in understanding the causes and mechanisms of unexplained miscarriage. https://doi.org/10.1289/EHP10477. 

BPDE, the Migration and Invasion of Human Trophoblast Cells, and Occurrence of Miscarriage in Humans: Roles of a Novel lncRNA-HZ09

Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NOP2/Sun domain family member 2 (NSUN2), which regulates the expression of p21 by binding to and causing the 5-methylcytidine methylation of the 3'- untranslated region of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging. 

OUP accepted manuscript

Significance The frequency discrimination important for animal communication and survival is achieved via a special functional arrangement of cells along the length of the cochlea. Hair cells at the base are tuned to high-frequency sounds, whereas those at the apex are tuned to lower frequencies. Gradual anatomical and physiological changes along the cochlea facilitate this frequency selectivity, but it remains unclear how this functional arrangement is established. Using mouse genetics, we found SHH specifies apical identity in the cochlear primordium. Then, SHH and FST together maintain cochlear cells with an apical fate. In the absence of FST or SHH, mice produce short cochleae lacking the apical domain, leading to low-frequency hearing loss.

Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals

The homeoprotein Msx1 cooperates with Pkn1 to prevent terminal differentiation in myogenic precursor cells.

Loss of homeoprotein Msx1 and Msx2 leading to athletic and kinematic impairment related to the increasing neural excitability of neurons in aberrant neocortex in mice.

Previous studies have shown that in myogenic precursors, the homeoprotein Msx1 and its protein partners, histone methyltransferases and repressive histone marks, tend to be enriched on target myogenic regulatory genes at the nuclear periphery. The nuclear periphery localization of Msx1 and its protein partners is required for Msx1’s function of preventing myogenic precursors from pre-maturation through repressing target myogenic regulatory genes. However, the mechanisms underlying the maintenance of Msx1 and its protein partners’ nuclear periphery localization are unknown. We show that an inner nuclear membrane protein, Emerin, performs as an anchor settled at the inner nuclear membrane to keep Msx1 and its protein partners Ezh2, H3K27me3 enriching at the nuclear periphery, and participates in inhibition of myogenesis mediated by Msx1. Msx1 interacts with Emerin both in C2C12 myoblasts and mouse developing limbs, which is the prerequisite for Emerin mediating the precise location of Msx1, Ezh2, and H3K27me3. The deficiency of Emerin in C2C12 myoblasts disturbs the nuclear periphery localization of Msx1, Ezh2, and H3K27me3, directly indicating Emerin functioning as an anchor. Furthermore, Emerin cooperates with Msx1 to repress target myogenic regulatory genes, and assists Msx1 with inhibition of myogenesis. Emerin cooperates with Msx1 to inhibit myogenesis through maintaining the nuclear periphery localization of Msx1 and Msx1’s protein partners.

/pdf/emerin-anchors-msx1-and-its-protein-partners-at-the-nuclear-2upexrn9bp.pdf

Emerin anchors Msx1 and its protein partners at the nuclear periphery to inhibit myogenesis.

Msh homeobox (Msx) is a subclass of homeobox transcriptional regulators that control cell lineage development, including the early stage of vertebrate limb development, although the underlying mechanisms are not clear. Here, we demonstrate that Msx1 promotes the proliferation of myoblasts and mesenchymal stem cells (MSCs) by enhancing mitogen-activated protein kinase (MAPK) signaling. Msx1 directly binds to and upregulates the expression of fibroblast growth factor 9 (Fgf9) and Fgf18. Accordingly, knockdown or antibody neutralization of Fgf9/18 inhibits Msx1-activated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Mechanistically, we determined that the phosphorylation of Msx1 at Ser136 is critical for enhancing Fgf9 and Fgf18 expression and cell proliferation, and cyclin-dependent kinase 1 (CDK1) is apparently responsible for Ser136 phosphorylation. Furthermore, mesenchymal deletion of Msx1/2 results in decreased Fgf9 and Fgf18 expression and Erk1/2 phosphorylation, which leads to serious defects in limb development in mice. Collectively, our findings established an important function of the Msx1-Fgf-MAPK signaling axis in promoting cell proliferation, thus providing a new mechanistic insight into limb development.

/pdf/phosphorylation-of-msx1-promotes-cell-proliferation-through-1fjtavbhrk.pdf

Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development.

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The homeoprotein Msx1 cooperates with Pkn1 to prevent terminal differentiation in myogenic precursor cells.

Loss of homeoprotein Msx1 and Msx2 leading to athletic and kinematic impairment related to the increasing neural excitability of neurons in aberrant neocortex in mice.

Emerin anchors Msx1 and its protein partners at the nuclear periphery to inhibit myogenesis.

Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development.