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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.07.005 Byline: Elona Kolpakova-Hart (a), Brandeis McBratney-Owen (a), Bo Hou (a), Naomi Fukai (a), Claudia Nicolae (a), Jing Zhou (b), Bjorn R. Olsen (a) Keywords: Craniofacial skeleton; Craniosynostosis; Cranial base; Synchondrosis; Suture; Polycystin-1 Abstract: In vertebrates, coordinated embryonic and postnatal growth of the craniofacial bones and the skull base is essential during the expansion of the rostrum and the brain. Identification of molecules that regulate skull growth is important for understanding the nature of craniofacial defects and for development of non-invasive biologically based diagnostics and therapies. Here we report on spatially restricted growth defects at the skull base and in craniofacial sutures of mice deficient for polycystin-1 (Pkd1). Mutant animals reveal a premature closure of both presphenoid and sphenooccipital synchondroses at the cranial base. Furthermore, knockout mice lacking Pkd1 in neural crest cells are characterized by impaired postnatal growth at the osteogenic fronts in craniofacial sutures that are subjected to tensile forces. Our data suggest that polycystin-1 is required for proliferation of subpopulations of cranial osteochondroprogenitor cells of both mesodermal and neural crest origin during skull growth. However, the Erk1/2 signalling pathway is up-regulated in the Pkd1-deficient skeletal tissue, similarly to that previously reported for polycystic kidney. Author Affiliation: (a) Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA (b) Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Article History: Received 9 January 2008; Revised 23 June 2008; Accepted 1 July 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.01.005 Byline: Donald J. Glotzer (a), Elazar Zelzer (b), Bjorn R. Olsen (a) Keywords: Runx2; Skin; Hair follicles; Mouse; Sonic hedgehog; Development; Gene expression; Hair cycle; Skin allograft; Skin thickness Abstract: The transcription factor, Runx2, is known to play crucial roles in skeletal and tooth morphogenesis. Here we document that Runx2 has a regulatory role in skin and hair follicle development. The expression of Runx2 is restricted to hair follicles and is dynamic, pari passu with follicle development. Follicle maturation is delayed in the absence of Runx2 and overall skin and epidermal thickness of Runx2 null embryos is significantly reduced. The Runx2 null epidermis is hypoplastic, displaying reduced expression of Keratin 14, Keratin 1 and markers of proliferation. The expression pattern of Runx2 in the bulb epithelium of mature hair follicles is asymmetric and strikingly similar to that of Sonic hedgehog. This suggests that Runx2 may be a regulator of hedgehog signaling in skin as it is in bones and teeth. Supporting this possibility, we demonstrate that Sonic hedgehog, Patched1 and Gli1 transcripts are reduced in the skin of Runx2 null embryos. Moreover, we document Patched1 expression in epidermal basal cells and show that the skin of Sonic.sup.+/- embryos is thinner than that of wild-type littermates. These observations suggest that Runx2 and hedgehog signaling are involved in the well known, but unexplained, coupling of skin thickness to hair follicle development. Author Affiliation: (a) Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA (b) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel Article History: Received 4 September 2007; Revised 11 December 2007; Accepted 3 January 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.07.018 Byline: Elona Kolpakova-Hart, Masatoshi Jinnin, Bo Hou, Naomi Fukai, Bjorn R. Olsen Keywords: Kinesin; Skeletal patterning; Hedgehog signaling; Intraflagellar transport Abstract: Hedgehog signaling plays an essential role in patterning of the vertebrate skeleton. Here we demonstrate that conditional inactivation of the Kif3a subunit of the kinesin-2 intraflagellar transport motor in mesenchymal skeletal progenitor cells results in severe patterning defects in the craniofacial area, the formation of split sternum and the development of polydactyly. These deformities are reminiscent of those previously described in mice with deregulated hedgehog signaling. We show that in Kif3a-deficient mesenchymal tissues both the repressor function of Gli3 transcription factor and the activation of the Shh transcriptional targets Ptch and Gli1 are compromised. Quantitative analysis of gene expression demonstrates that the Gli1 transcript level is dramatically reduced, whereas Gli3 expression is not significantly affected by kinesin-2 depletion. However, the motor appears to be required for the efficient cleavage of the full-length Gli3 transcription factor into a repressor form. Author Affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA Article History: Received 7 May 2007; Revised 10 July 2007; Accepted 14 July 2007