OSTM1 regulates β-catenin/Lef1 interaction and is required for Wnt/β-catenin signaling

Abstract

The Wnt/β-catenin signaling pathway controls key aspects of embryonic development and adult tissue homeostasis, including the formation and maintenance of bone. Recently, mutations in the OSTM1 gene were found to be the cause of severe autosomal recessive osteopetrosis in both the mouse and humans. This disorder is characterized by increased bone mass resulting from a defect in osteoclast maturation. The possible role of OSTM1 in signaling of the Wnt/β-catenin "canonical" pathway was investigated in totipotent mouse F9 embryonal teratocarcinoma cells. Overexpression of OSTM1 in F9 cells increased Wnt3a-responsive β-catenin accumulation and Lef/Tcf-sensitive transcription. Similarly, knockdown of endogenous OSTM1 attenuated the ability of Wnt3a to stimulate the canonical signaling pathway. An OSTM1 mutant (detected in humans with osteopetrosis) was expressed in F9 cells and found to inhibit Wntstimulated β-catenin stabilization, gene transcription, and primitive endoderm formation. Expression of this OSTM1 C-terminal deletion mutant attenuated Lef/Tcf-sensitive gene transcription, even when transcription was activated by expression of a constitutively-active form of β-catenin. However, expression of this OSTM1 C-terminal deletion mutant was unable to alter Lef/Tcf-sensitive gene transcription when transcription was activated by expression of a β-catenin/Lef chimeric protein.From the standpoint of protein-protein interactions, expression of wild-type OSTM1 stimulated whereas mutant OSTM1 inhibited, the Wnt-dependent association of β-catenin and Lef1. On the foundation of these experiments, we propose that the human mutations in OSTM1 such as the Cterminal deletion mutant studied herein provoke dysregulation of the canonical Wnt/β-catenin signaling pathway, providing a molecular basis for severe autosomal recessive osteopetrosis.

MicroRNA-140 Promotes Adipocyte Lineage Commitment of C3H10T1/2 Pluripotent Stem Cells via Targeting Osteopetrosis-associated Transmembrane Protein 1

“…Previous studies elucidated three biological functions of OSTM1: it serves as a ␤-subunit of ClC-7 to support bone resorption and lysosomal function, it works as an E3 ubiquitin ligase to induce proteasome-dependent degradation of G␣ i3 , and it promotes ␤-catenin/Lef1 interaction (22)(23)(24). The above findings suggest that OSTM1 has an important role in bone development.…”

Loss of PPARγ in endothelial cells leads to impaired angiogenesis

“…OSTM1 encodes a type 1 transmembrane protein, which is localized in intracellular vesicles. OSTM1 enhances Wnt signaling by regulating β-catenin-Lef1 interaction and, when downregulated, suppresses the Wnt-β-catenin pathway (Feigin and Malbon, 2008). GSKIP is known to promote cell-cycle progression in neuronal cells by increasing the nuclear accumulation of β-catenin by inactivating GSK3β (also known as GSK3B) (Chou et al, 2006;Lin et al, 2009).…”

Totipotency: What It Is and What It Is Not

“…The authors present no evidence that isolated 2C-like cells are capable of generating embryos on their own and are careful not to pronounce their 2C-like cells totipotent in the organismal sense, but the repeated observation that the 2C stage correlates with a period in which ''blastomeres are totipotent'' [14] is strongly suggestive of this unwarranted conclusion and illustrates the confusing usage of the term ''totipotent'' in the scientific literature. Similarly, the ability of stem cells [3,4] or carcinomas [1,2] to express a molecular marker of ''extraembryonic'' cell lineages in addition to markers associated with ICM has been taken as evidence of totipotency, despite there being no indication that these cells can initiate a developmental sequence on their own.…”

“…Much of the confusion surrounding the term totipotency centers on the important differences between these two definitions. A one-cell embryo (zygote) is ''totipotent'' in both senses; yet, some authors characterize tumors [1,2] and stem cells [3,4] as ''totipotent,'' based only on the second definition (ie, the ability of these cells to produce a wide range of cell types).…”