Twist1-Haploinsufficiency Selectively Enhances the Osteoskeletal Capacity of Mesoderm-Derived Parietal Bone Through Downregulation of Fgf23

Craniofacial development is a program exquisitely orchestrated by tissue contributions and regulation of genes expression. The basic helix–loop–helix (bHLH) transcription factor Twist1 expressed in the skeletal mesenchyme is a key regulator of craniofacial development playing an important role during osteoskeletogenesis. This study investigates the postnatal impact of Twist1 haploinsufficiency on the osteoskeletal ability and regeneration on two calvarial bones arising from tissues of different embryonic origin: the neural crest-derived frontal and the mesoderm-derived parietal bones. We show that Twist1 haplonsufficiency as well Twist1-sh-mediated silencing selectively enhanced osteogenic and tissue regeneration ability of mesoderm-derived bones. Transcriptomic profiling, gain-and loss-of-function experiments revealed that Twist1 haplonsufficiency triggers its selective activity on mesoderm-derived bone through a sharp downregulation of the bone-derived hormone Fgf23 that is upregulated exclusively in wild-type parietal bone

Clouston syndrome with pili canaliculi, pili torti, overgrown hyponychium, onycholysis, taurodontism and absence of palmoplantar keratoderma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155882/1/jde15333.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155882/2/jde15333_am.pd

Treacher Collins syndrome: A novel TCOF1 mutation and monopodial stapes

Treacher Collins syndrome (TCS: OMIM 154500) is an autosomal dominant craniofacial disorder belonging to the heterogeneous group of mandibulofacial dysostoses.ObjectiveTo investigate four Treacher Collins syndrome patients of the Sgaw Karen family living in Thailand.MethodClinical examination, hearing tests, lateral cephalometric analyses, Computed tomography, whole exome sequencing and Sanger direct sequencing were performed.ResultsAll of the patients affected with Treacher Collins syndrome carried a novel TCOF1 mutation (c.4138_4142del; p.Lys1380GlufsTer12), but clinically they did not have the typical facial gestalt of Treacher Collins syndrome, which includes downward‐slanting palpebral fissures, colobomas of the lower eyelids, absence of eyelashes medial to the colobomas, malformed pinnae, hypoplastic zygomatic bones and mandibular hypoplasia. Lateral cephalometric analyses identified short anterior and posterior cranial bases, and hypoplastic maxilla and mandible. Computed tomography showed fusion of malleus and incus, sclerotic mastoid, hypoplastic middle ear space with a soft tissue remnant, dehiscence of facial nerve and monopodial stapes.ConclusionTreacher Collins syndrome in Sgaw Karen patients has not been previously documented. This is the first report of monopodial stapes in a TCS patient who had a TCOF1 mutation. The absence of a common facial phenotype and/or the presence of monopodial stapes may be the effects of this novel TCOF1 mutation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156466/2/coa13560.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156466/1/coa13560_am.pd

TRPS1 mutation associated with trichorhinophalangeal syndrome type 1 with 15 supernumerary teeth, hypoplastic mandibular condyles with slender condylar necks and unique hair morphology

Trichorhinophalangeal syndrome type 1 (TRPS1; Online Mendelian Inheritance in Man #190350) is an autosomal dominant disorder caused by mutations in TRPS1. We report a Thai male with TRPS1 who carried a c.1842C>T (p.Arg615Ter) mutation. He had 15 supernumerary teeth, double mental foramina, hypoplastic mandibular condyles with slender condylar necks and unique ultrastructural hair findings. Body hair was absent. The hair in the area of a congenital melanocytic nevus had a greater number of hair cuticles than normal. Occipital hair had abnormal hair follicles and cuticles. The scale edges of the hair cuticles were detached and rolled up. Hypoplastic mandibular condyles with slender condylar necks, double mental foramina and the rolled up edges of hair cuticles have not been reported in patients with TRPS1.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155929/1/jde15360.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155929/2/jde15360_am.pd

Activation of FGF Signaling Mediates Proliferative and Osteogenic Differences between Neural Crest Derived Frontal and Mesoderm Parietal Derived Bone

BACKGROUND: As a culmination of efforts over the last years, our knowledge of the embryonic origins of the mammalian frontal and parietal cranial bones is unambiguous. Progenitor cells that subsequently give rise to frontal bone are of neural crest origin, while parietal bone progenitors arise from paraxial mesoderm. Given the unique qualities of neural crest cells and the clear delineation of the embryonic origins of the calvarial bones, we sought to determine whether mouse neural crest derived frontal bone differs in biology from mesoderm derived parietal bone. METHODS: BrdU incorporation, immunoblotting and osteogenic differentiation assays were performed to investigate the proliferative rate and osteogenic potential of embryonic and postnatal osteoblasts derived from mouse frontal and parietal bones. Co-culture experiments and treatment with conditioned medium harvested from both types of osteoblasts were performed to investigate potential interactions between the two different tissue origin osteoblasts. Immunoblotting techniques were used to investigate the endogenous level of FGF-2 and the activation of three major FGF signaling pathways. Knockdown of FGF Receptor 1 (FgfR1) was employed to inactivate the FGF signaling. RESULTS: Our results demonstrated that striking differences in cell proliferation and osteogenic differentiation between the frontal and parietal bone can be detected already at embryonic stages. The greater proliferation rate, as well as osteogenic capacity of frontal bone derived osteoblasts, were paralleled by an elevated level of FGF-2 protein synthesis. Moreover, an enhanced activation of FGF-signaling pathways was observed in frontal bone derived osteoblasts. Finally, the greater osteogenic potential of frontal derived osteoblasts was dramatically impaired by knocking down FgfR1. CONCLUSIONS: Osteoblasts from mouse neural crest derived frontal bone displayed a greater proliferative and osteogenic potential and endogenous enhanced activation of FGF signaling compared to osteoblasts from mesoderm derived parietal bone. FGF signaling plays a key role in determining biological differences between the two types of osteoblasts

Temporal and spatial expression of RNases from zebrafish (Danio rerio).

In the present study we have analyzed the temporal and spatial gene expression profiles of three zebrafish (Danio rerio) RNases endowed with diverse bioactivities, including microbicidal and angiogenic activities. Our results indicate that the three ZF-RNase genes have a differential expression pattern, with ZF-RNase-1 having the most unique and dynamic expression profile. This is characterized by expression in embryonic stages and later on, in larvae, juvenile and adult organisms. In contrast, ZF-RNase-2 and -3 are only expressed either in juvenile or adult organisms. Moreover, analysis of spatial expression of ZF-RNase-1, -2 and -3 detected the three different transcripts in liver, heart, gut and swim bladder tissues. Interestingly, ZF-RNase-1 was the only gene expressed in the brain of embryonic and adult organisms. Collectively, the results suggest that the three ZF-RNases may have potential distinct functional role(s) in zebrafish either during embryonic development and/or later on, in juvenile as well as in adult organisms. Indeed, taking advantage of zebrafish as an excellent viable model to study gene function, this study opens the way to an investigation of the in vivo role(s) of ZF-RNase-1 during embryonic development, as well as, during organogenesis

Absence of endochondral ossification and craniosynostosis in posterior frontal cranial sutures of Axin2(-/-) mice.

During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through endochondral ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable endochondral ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2(-/-) mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2(-/-) PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological endochondral ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2(-/-) PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2(-/-) PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2(-/-) PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2(-/-) PF-sutures lack physiological endochondral ossification, contain ectopic cartilage and display delayed suture closure