Inactivation Alters Subcutaneous Tissues in Progression to Heterotopic Ossification.

Heterotopic ossification (HO), the formation of bone outside of the skeleton, occurs in response to severe trauma and in rare genetic diseases such as progressive osseous heteroplasia (POH). In POH, which is caused by inactivation of , a gene that encodes the alpha stimulatory subunit of G proteins (Gsα), HO typically initiates within subcutaneous soft tissues before progressing to deeper connective tissues. To mimic POH, we used conditional -null mice which form HO in subcutaneous tissues upon inactivation.

Progressive osseous heteroplasia: diagnosis, treatment, and prognosis.

Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS.

EGF induces efficient Cx43 gap junction endocytosis in mouse embryonic stem cell colonies via phosphorylation of Ser262, Ser279/282, and Ser368.

Gap junctions (GJs) traverse apposing membranes of neighboring cells to mediate intercellular communication by passive diffusion of signaling molecules. We have shown previously that cells endocytose GJs utilizing the clathrin machinery. Endocytosis generates cytoplasmic double-membrane vesicles termed annular gap junctions or connexosomes.

Two tyrosine-based sorting signals in the Cx43 C-terminus cooperate to mediate gap junction endocytosis.

Gap junction (GJ) channels that electrically and chemically couple neighboring cells are formed when two hemichannels (connexons) of apposed cells dock head-on in the extracellular space. Remarkably, docked connexons are inseparable under physiological conditions, and we and others have shown that GJs are internalized in whole, utilizing the endocytic clathrin machinery. Endocytosis generates double-membrane vesicles (annular GJs or connexosomes) in the cytoplasm of one of the apposed cells that are degraded by autophagosomal and, potentially, endo/lysosomal pathways.

Proteins and mechanisms regulating gap-junction assembly, internalization, and degradation.

Gap junctions (GJs) are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays or "plaques" of hydrophilic channels that bridge the apposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for all aspects of multicellular life, including coordination of development, tissue function, and cell homeostasis, has been well documented. Assembly and degradation of these membrane channels is a complex process that includes biosynthesis of the connexin (Cx) subunit proteins (innexins in invertebrates) on endoplasmic reticulum (ER) membranes, oligomerization of compatible subunits into hexameric hemichannels (connexons), delivery of the connexons to the plasma membrane (PM), head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic spatially and temporally organized GJ channel plaques, as well as internalization of GJs into the cytoplasm followed by their degradation.

Degradation of endocytosed gap junctions by autophagosomal and endo-/lysosomal pathways: a perspective.

Gap junctions (GJs) are composed of tens to many thousands of double-membrane spanning GJ channels that cluster together to form densely packed channel arrays (termed GJ plaques) in apposing plasma membranes of neighboring cells. In addition to providing direct intercellular communication (GJIC, their hallmark function), GJs, based on their characteristic double-membrane-spanning configuration, likely also significantly contribute to physical cell-to-cell adhesion. Clearly, modulation (up-/down-regulation) of GJIC and of physical cell-to-cell adhesion is as vitally important as the basic ability of GJ formation itself.

Internalized gap junctions are degraded by autophagy.

Direct intercellular communication mediated by gap junctions (GJs) is a hallmark of normal cell and tissue physiology. In addition, GJs significantly contribute to physical cell-cell adhesion. Clearly, these cellular functions require precise modulation.