Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus

Chen, Xiaoyan; Wang, Huiming; Yu, Miao; Kim, Jong Kil; Qi, Huichuan; Ha, Pin; Jiang, Wenlu; Chen, Eric; Luo, Xiangyou; Needle, Ryan Brent; Baik, Lloyd; Yang, Cathryn; Shi, Jiejun; Kwak, Jin Hee; Ting, Kang; Zhang, Xinli

doi:10.1038/s41418-019-0427-1

Cited by 8 publications

(14 citation statements)

References 70 publications

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“…The O9-1 cell line (Sigma Millipore, Cat# SCC049) was cultured in cell culture flasks pre-coated with 1:50 diluted Matrigel TM (Fisher, Cat# CB-40234) at room temperature for 1 hour; then cells were grown in complete ES cell medium with 15% FBS and LIF (Sigma Millipore, Cat# ES-101-B) + 25 ng/ml recombinant human bFGF (Sigma Millipore, Cat# GF003) at 37 °C, 5% CO 2 . Primary mouse CNCCs were isolated from the frontal and nasal bones of the cranial vault of neonatal wildtype C57BL/6J mouse, following the established protocol (Chen et al, 2019;Wong and Cohn, 1975;Zhang et al, 2002). They were cultured in growth medium containing high glucose DMEM + 10% heat-inactivated fetal bovine serum (FBS) + 100 U/ml penicillin/streptomycin (P/S) at 37 °C, 5% CO 2 .…”

Section: Cell Culturementioning

confidence: 99%

Physiological electric fields induce directional migration of mammalian cranial neural crest cells

Mehta

Zhu

et al. 2021

Developmental Biology

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During neurulation, cranial neural crest cells (CNCCs) migrate long distances from the neural tube to their terminal site of differentiation. The pathway traveled by the CNCCs defines the blueprint for craniofacial construction, abnormalities of which contribute to three-quarters of human birth defects. Biophysical cues like naturally occurring electric fields (EFs) have been proposed to be one of the guiding mechanisms for CNCC migration from the neural tube to identified position in the branchial arches. Such endogenous EFs can be mimicked by applied EFs of physiological strength that has been reported to guide the migration of amphibian and avian neural crest cells (NCCs), namely galvanotaxis or electrotaxis. However, the behavior of mammalian NCCs in external EFs has not been reported. We show here that mammalian CNCCs migrate towards the anode in direct current (dc) EFs. Reversal of the field polarity reverses the directedness.The response threshold was below 30mV/mm and the migration directedness and displacement speed increased with increase of field strength. Both CNCC line (O9-1) and primary mouse CNCCs show similar galvanotaxis behavior. Our results demonstrate for the first time that the mammalian CNCCs respond to physiological EFs by robust directional migration towards the anode in a voltage-dependent manner.

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Section: Cell Culturementioning

confidence: 99%

Physiological electric fields induce directional migration of mammalian cranial neural crest cells

Mehta

Zhu

et al. 2021

Developmental Biology

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“…Recent evidence has shown that BMP9 functions at the fracture site, at the same time, BMP9 can function as an inductive signal to maintain proliferative capacities of suture-derived stem cells in the long term to differentiate into osteogenic lineages in vivo and in vitro (Song et al, 2017). More interestingly, BMP9 regulates Nell-1 activity, which is an osteo-inductive growth factor, and mutant Nell-1 results in significant cranial abnormalities (Song et al, 2017;Chen et al, 2019b). In our early publication, we found that Nell-1 in neural-crest-derived frontal bone is significantly expressed compared to that in mesoderm-derived parietal bones (Hu et al, 2017).…”

Section: Bmp Signaling In Calvarial Regeneration Bmps and Calvarial Rmentioning

confidence: 99%

BMP Signaling in the Development and Regeneration of Cranium Bones and Maintenance of Calvarial Stem Cells

Chen

Yao

et al. 2020

Front. Cell Dev. Biol.

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The bone morphogenetic protein (BMP) signaling pathway is highly conserved across many species, and its importance for the patterning of the skeletal system has been demonstrated. A disrupted BMP signaling pathway results in severe skeletal defects. Murine calvaria has been identified to have dual-tissue lineages, namely, the cranial neural-crest cells and the paraxial mesoderm. Modulations of the BMP signaling pathway have been demonstrated to be significant in determining calvarial osteogenic potentials and ossification in vitro and in vivo. More importantly, the BMP signaling pathway plays a role in the maintenance of the homeostasis of the calvarial stem cells, indicating a potential clinic significance in calvarial bone and in expediting regeneration. Following the inherent evidence of BMP signaling in craniofacial biology, we summarize recent discoveries relating to BMP signaling in the development of calvarial structures, functions of the suture stem cells and their niche and regeneration. This review will not only provide a better understanding of BMP signaling in cranial biology, but also exhibit the molecular targets of BMP signaling that possess clinical potential for tissue regeneration.

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“…Mechanistically, these phenotypic changes are likely the results of inhibition of Ihh signaling and alternation of the Ihh-PTHrP feedback loop in chondrocytes of the growth plate (Qi et al 2019; Table 1). In addition to the cell-autonomous effects of Nell-1 inactivation in cranial neural crest cells and chondrocytes in Nell-1 Wnt1 KO and Nell-1 Col2a1 KO mice, respectively, the non–cell autonomous influences on osteoclasts have been observed in both mutant mouse lines, with significantly higher levels of TRAP staining detected in calvarial and mandibular bones in neonatal Nell-1 Wnt1 KO mice and in metaphyseal trabecular bones in 1- and 3-mo-old Nell-1 Col2α1 KO mice (Chen et al 2019; Qi et al 2019). However, the underlying mechanisms of the non–cell autonomous effects of Nell-1 inactivation remain left to be investigated in future studies.…”

Section: Indispensable Role Of Nell-1 For Normal Skeletal Developmentmentioning

confidence: 99%

“…Some Nell-1 Wnt1 KO mice developed hydrocephalus at around 40 d old, accompanied with a shorter life span, short body length, and premature ossification and fusion of cranial base synchondrosis. This modulatory role of Nell-1 on cranial neural crest cells is partial via activating the Wnt/β-catenin pathway (Chen et al 2019). With the deleted Nell-1 gene in the preosteoblastic cell lineages, the Nell-1 Col1 KO mice again represented a delayed fusion of cranial sutures.…”

Section: Indispensable Role Of Nell-1 For Normal Skeletal Developmentmentioning

confidence: 99%

“…References Zhang et al 2002;Zhang et al 2006Desai et al 2006Zhang et al 2012;James et al 2015;Qin et al 2016;James et al 2017James et al 2017Chen et al 2019Chen et al 2019 Unpublished data Qi et al 2019 BMD, bone mineral density; BV/TV, bone volume/total volume; CDD, cleidocranial dysplasia; CMV, cytomegalovirus; CS, craniosynostosis; Ct.Th., average cortical thickness; ENU, N-ethyl-N-nitrosourea; KO, knockout; MPC, mesenchymal progenitor cell; NTD, neural tube defect; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; WT, wild type. Nell-1 deficiency (James et al 2017).…”

Section: Not Analyzedmentioning

confidence: 99%

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Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond

Zhang

Zheng

et al. 2019

J Dent Res

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Neural EGFL-like 1 (Nell-1) is a well-studied osteogenic factor that has comparable osteogenic potency with the Food and Drug Administration–approved bone morphogenic protein 2 (BMP-2). In this review, which aims to summarize the advanced Nell-1 research in the past 10 y, we start with the correlation of structural and functional relevance of the Nell-1 protein with the identification of a specific receptor of Nell-1, contactin-associated protein-like 4 (Cntnap4), for osteogenesis. The indispensable role of Nell-1 in normal craniofacial and appendicular skeletal development and growth was also defined by using the newly developed tissue-specific Nell-1 knockout mouse lines in addition to the existing transgenic mouse models. With the achievements on Nell-1’s osteogenic therapeutic evaluations from multiple preclinical animal models for local and systemic bone regeneration, the synergistic effect of Nell-1 with BMP-2 on osteogenesis, as well as the advantages of Nell-1 as an osteogenic protein with antiadipogenic, anti-inflammatory, and provascularized characteristics over BMP-2 in bone tissue engineering, is highlighted, which lays the groundwork for the clinical trial approval of Nell-1. At the molecular level, besides the mitogen-activated protein kinase (MAPK) signaling pathway, we emphasize the significant involvement of the Wnt/β-catenin pathway as well as the key regulatory molecules Runt-related transcription factor 2 (Runx2) in Nell-1-induced osteogenesis. In addition, the involvement of Nell-1 in chondrogenesis and its relevant pathologies have been revealed with the participation of the nuclear factor of activated T cells 1 (Nfatc1), Runx3, and Indian hedgehog (Ihh) signaling pathways, although the mechanistic insights of Nell-1’s osteochondrogenic property will be continuously evolving. With this perspective, we elucidate some emerging and novel functional properties of Nell-1 in oral-dental and neural tissues that will be the frontiers of future Nell-1 studies beyond the context of bone and cartilage. As such, the therapeutic potential of Nell-1 continues to evolve and grow with continuous pursuit.

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Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus

Cited by 8 publications

References 70 publications

Physiological electric fields induce directional migration of mammalian cranial neural crest cells

Physiological electric fields induce directional migration of mammalian cranial neural crest cells

BMP Signaling in the Development and Regeneration of Cranium Bones and Maintenance of Calvarial Stem Cells

Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond

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