Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis

Liu, Ying; Snedecor, Elizabeth R.; Choi, Yeon Ja; Yang, Ning; Zhang, Xu; Xu, Yuhuan; Han, Yunlin; Jones, Evan; Shroyer, Kenneth R.; Clark, Richard A.F.; Zhang, Lianfeng; Qin, Chuan; Chen, Jiang

doi:10.1016/j.jid.2015.10.067

Cited by 16 publications

(23 citation statements)

References 49 publications

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“…Both mouse lines, which are in the following referred to as Gorab Null , showed an identical phenotype with absence of skin changes reminiscent of cutis laxa, but early lethality due to respiratory distress, most likely secondary to decreased alveolar airspace ( S2A–S2D Fig ). This is in line with an independent description of Gorab Null mice [ 12 ]. Apart from enlarged fontanels no significant skeletal abnormalities were identified ( S3A–S3E Fig ).…”

Section: Resultssupporting

confidence: 91%

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

et al. 2018

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Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

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Section: Resultssupporting

confidence: 91%

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

et al. 2018

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“…The nearest gene to rs80715313 on GGA8 is GORAB that encodes SCY1-like 1-binding protein 1, which localizes predominantly to the trans Golgi network [ 47 ], where it performs important functions in the secretory and endocytic pathways [ 48 ]. The abundance of glandular tissue in the oviduct is involved in protein secretion [ 49 ], and ovalbumin and ovotransferrin are transported from the Golgi complex to the plasmalemma by microtubules [ 50 ], which combined with the result from the genotypic effect of rs80715313 on albumen height, suggests that GORAB may have effects on the secretion of egg white proteins during egg formation.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide study to identify genes responsible for oviduct development in chickens

Shen

et al. 2017

PLoS ONE

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Molecular genetic tools provide a method for improving the breeding selection of chickens (Gallus gallus). Although some studies have identified genes affecting egg quality, little is known about the genes responsible for oviduct development. To address this issue, here we used a genome-wide association (GWA) study to detect genes or genomic regions that are related to oviduct development in a chicken F2 resource population by employing high-density 600 K single-nucleotide polymorphism (SNP) arrays. For oviduct length and weight, which exhibited moderate heritability estimates of 0.35 and 0.39, respectively, chromosome 1 (GGA1) explained 9.45% of the genetic variance, while GGA4 to GGA8 and GGA11 explained over 1% of the variance. Independent univariate genome-wide screens for oviduct length and weight detected 69 significant SNPs on GGA1 and 49 suggestive SNPs on GGA1, GGA4, and GGA8. One hundred and fourteen suggestive SNPs were associated with oviduct length, while 73 SNPs were associated with oviduct weight. The significant genomic regions affecting oviduct weight ranged from 167.79–174.29 Mb on GGA1, 73.16–75.70 Mb on GGA4, and 4.88–4.92 Mb on GGA8. The genes CKAP2, CCKAR, NCAPG, IGFBP3, and GORAB were shown to have potential roles in oviduct development. These genes are involved in cell survival, appetite, and growth control. Our results represent the first GWA analysis of genes controlling oviduct weight and length. The identification of genomic loci and potential candidate genes affecting oviduct development greatly increase our understanding of the genetic basis underlying oviduct development, which could have an impact on the selection of egg quality.

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“…Such tissue specificity may not be confined to flies and indeed, our present study may help clarify some recent observations about the function of the mammalian GORAB protein. A GORAB mutant mouse was recently generated that shows defects in hair follicle morphogenesis correlating with mild defects in Hedgehog (Hh) signaling 41 . These mice have few primary cilia in dermal condensate cells responsible for Hh signaling in hair follicles but do have primary cilia on keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

GORAB, a Golgi protein required for centriole structure and duplication

Kovács

Chao-Chu

Schneider

et al. 2017

Preprint

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Genome wide screens are widely believed to have identified the great majority of genes required for centriole duplication. However, seeking to clarify the partners of the Drosophila cartwheel protein Sas6, we identified Gorab, a known trans-Golgi associated protein that is mutated in the human wrinkly skin disease, gerodermia osteodysplastica. We now report that Gorab is present not only in the trans-Golgi but also in association with Sas6 at the core of the centriole. Flies lacking Gorab show defects in centriole duplication in many tissues and are also uncoordinated due to basal body defects in sensory cilia, which lose their 9-fold symmetry. We demonstrate the separation of centriole and Golgi functions of Drosophila Gorab in two ways: First, we have created Gorab variants that are unable to localize to trans-Golgi but can still rescue the centriole and cilia defects of gorab null flies. Secondly, we show that expression of Cterminally tagged Gorab disrupts Golgi functions in cytokinesis of male meiosis, a dominant phenotype overcome by a second mutation preventing Golgi targeting. We discuss the tissue specific requirement of Gorab for centriole duplication in the context of its split functions.

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Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis

Cited by 16 publications

References 49 publications

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

A genome-wide study to identify genes responsible for oviduct development in chickens

GORAB, a Golgi protein required for centriole structure and duplication

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