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Molecular Mechanisms of Craniofacial Birth Defects
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Molecular Mechanisms of Craniofacial Birth Defects

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 10152

Special Issue Editors

Dr. Akiko Suzuki

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Guest Editor
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA
Interests: developmental biology; craniofacial development and disorder; microRNA; membrane trafficking
Dr. Junichi Iwata

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Guest Editor
Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
Interests: craniofacial development; cell signaling; membrane trafficking; cellular metabolism; noncoding RNAs; muscle development and regeneration
Special Issues, Collections and Topics in MDPI journals
Dr. Yoshihiro Komatsu

E-Mail Website
Guest Editor
Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA
Interests: bone development; ciliopathy; craniofacial development; mouse development and genetics; stem cells

Special Issue Information

Dear Colleagues,

The craniofacial structure is composed of multiple tissues and organs, including bones, cartilage, muscles, neuronal/nervous systems, exocrine glands, and teeth, and their malformations including craniosynostosis, facial microsomia, cleft lip with/without cleft palate, tooth agenesis, and amelogenesis/dentinogenesis imperfecta are among the most common congenital birth defects. The etiology of these malformations is the contribution of either genetic factors (isolated or syndromic), environmental factors, or both. Previous studies have revealed that hundreds of genetic mutations and their epigenetic modifications are associated with craniofacial birth defects. In addition, since multiple cell lineages contribute to the formation of craniofacial structures, their regulation through cell-autonomous and non-cell-autonomous mechanisms in a temporospatial manner is important. However, the cellular and molecular mechanisms behind gene regulatory networks remain largely unknown. Recently, the modulation of gene regulatory networks by pharmacological approaches has interested basic and clinical researchers as a strategy for the prevention of craniofacial malformations. This Special Issue focuses on the current understanding and new findings regarding the regulation of gene expression, signaling cascades, and patterning of cells during craniofacial development and in birth defects. 

Dr. Akiko Suzuki
Dr. Junichi Iwata
Dr. Yoshihiro Komatsu
Guest Editors

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Keywords

  • craniofacial development
  • congenital birth defect
  • gene regulatory network
  • single-nucleotide polymorphism
  • epigenetic modification
  • non-coding RNA
  • human genetics
  • mouse genetics

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Published Papers (4 papers)

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Research

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21 pages, 20183 KiB  
Article
Cranial Neural Crest Specific Deletion of Alpl (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth
by Naoto Ohkura, Hwa Kyung Nam, Fei Liu and Nan Hatch
Int. J. Mol. Sci. 2023, 24(20), 15401; https://doi.org/10.3390/ijms242015401 - 20 Oct 2023
Viewed by 1823
Abstract
Bone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, Alpl) enzyme activity. The abnormal development of the cranial base growth plates (synchondroses) [...] Read more.
Bone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, Alpl) enzyme activity. The abnormal development of the cranial base growth plates (synchondroses) and abnormal skull shapes have also been demonstrated in global Alpl−/− mice. To distinguish local vs. systemic effects of TNAP on skull development, we utilized P0-Cre to knockout Alpl only in cranial neural crest-derived tissues using Alpl flox mice. Here, we show that Alpl deficiency using P0-Cre in cranial neural crest leads to skull shape defects and the deficient growth of the intersphenoid synchondrosis (ISS). ISS chondrocyte abnormalities included increased proliferation in resting and proliferative zones with decreased apoptosis in hypertrophic zones. ColX expression was increased, which is indicative of premature differentiation in the absence of Alpl. Sox9 expression was increased in both the resting and prehypertrophic zones of mutant mice. The expression of Parathyroid hormone related protein (PTHrP) and Indian hedgehog homolog (IHH) were also increased. Finally, cranial base organ culture revealed that inorganic phosphate (Pi) and pyrophosphate (PPi) have specific effects on cell signaling and phenotype changes in the ISS. Together, these results demonstrate that the TNAP expression downstream of Alpl in growth plate chondrocytes is essential for normal development, and that the mechanism likely involves Sox9, PTHrP, IHH and PPi. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Craniofacial Birth Defects)
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16 pages, 22816 KiB  
Article
Deficiency of Fam20b-Catalyzed Glycosaminoglycan Chain Synthesis in Neural Crest Leads to Cleft Palate
by Xiaoyan Chen, Nan Li, Ping Hu, Leilei Li, Danya Li, Han Liu, Lei Zhu, Jing Xiao and Chao Liu
Int. J. Mol. Sci. 2023, 24(11), 9634; https://doi.org/10.3390/ijms24119634 - 1 Jun 2023
Cited by 1 | Viewed by 1724
Abstract
Cleft palate is one of the most common birth defects. Previous studies revealed that multiple factors, including impaired intracellular or intercellular signals, and incoordination of oral organs led to cleft palate, but were little concerned about the contribution of the extracellular matrix (ECM) [...] Read more.
Cleft palate is one of the most common birth defects. Previous studies revealed that multiple factors, including impaired intracellular or intercellular signals, and incoordination of oral organs led to cleft palate, but were little concerned about the contribution of the extracellular matrix (ECM) during palatogenesis. Proteoglycans (PGs) are one of the important macromolecules in the ECM. They exert biological functions through one or more glycosaminoglycan (GAG) chains attached to core proteins. The family with sequence similarity 20 member b (Fam20b) are newly identified kinase-phosphorylating xylose residues that promote the correct assembly of the tetrasaccharide linkage region by creating a premise for GAG chain elongation. In this study, we explored the function of GAG chains in palate development through Wnt1-Cre; Fam20bf/f mice, which exhibited complete cleft palate, malformed tongue, and micrognathia. In contrast, Osr2-Cre; Fam20bf/f mice, in which Fam20b was deleted only in palatal mesenchyme, showed no abnormality, suggesting that failed palatal elevation in Wnt1-Cre; Fam20bf/f mice was secondary to micrognathia. In addition, the reduced GAG chains promoted the apoptosis of palatal cells, primarily resulting in reduced cell density and decreased palatal volume. The suppressed BMP signaling and reduced mineralization indicated an impaired osteogenesis of palatine, which could be rescued partially by constitutively active Bmpr1a. Together, our study highlighted the key role of GAG chains in palate morphogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Craniofacial Birth Defects)
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19 pages, 1556 KiB  
Article
A Comprehensive Genetic Analysis of Slovenian Families with Multiple Cases of Orofacial Clefts Reveals Novel Variants in the Genes IRF6, GRHL3, and TBX22
by Lara Slavec, Ksenija Geršak, Andreja Eberlinc, Tinka Hovnik, Luca Lovrečić, Irena Mlinarič-Raščan and Nataša Karas Kuželički
Int. J. Mol. Sci. 2023, 24(5), 4262; https://doi.org/10.3390/ijms24054262 - 21 Feb 2023
Cited by 1 | Viewed by 2593
Abstract
Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1; VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only [...] Read more.
Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1; VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only minor clinical signs in addition to OFC and are sometimes difficult to differentiate from nsOFCs. We recruited 34 Slovenian multi-case families with apparent nsOFCs (isolated OFCs or OFCs with minor additional facial signs). First, we examined IRF6, GRHL3, and TBX22 by Sanger or whole exome sequencing to identify VWS and CPX families. Next, we examined 72 additional nsOFC genes in the remaining families. Variant validation and co-segregation analysis were performed for each identified variant using Sanger sequencing, real-time quantitative PCR and microarray-based comparative genomic hybridization. We identified six disease-causing variants (three novel) in IRF6, GRHL3, and TBX22 in 21% of families with apparent nsOFCs, suggesting that our sequencing approach is useful for distinguishing syOFCs from nsOFCs. The novel variants, a frameshift variant in exon 7 of IRF6, a splice-altering variant in GRHL3, and a deletion of the coding exons of TBX22, indicate VWS1, VWS2, and CPX, respectively. We also identified five rare variants in nsOFC genes in families without VWS or CPX, but they could not be conclusively linked to nsOFC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Craniofacial Birth Defects)
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Review

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22 pages, 2130 KiB  
Review
Molecular Mechanisms of Craniofacial and Dental Abnormalities in Osteopetrosis
by Yu Ma, Yali Xu, Yanli Zhang and Xiaohong Duan
Int. J. Mol. Sci. 2023, 24(12), 10412; https://doi.org/10.3390/ijms241210412 - 20 Jun 2023
Cited by 5 | Viewed by 2825
Abstract
Osteopetrosis is a group of genetic bone disorders characterized by increased bone density and defective bone resorption. Osteopetrosis presents a series of clinical manifestations, including craniofacial deformities and dental problems. However, few previous reports have focused on the features of craniofacial and dental [...] Read more.
Osteopetrosis is a group of genetic bone disorders characterized by increased bone density and defective bone resorption. Osteopetrosis presents a series of clinical manifestations, including craniofacial deformities and dental problems. However, few previous reports have focused on the features of craniofacial and dental problems in osteopetrosis. In this review, we go through the clinical features, types, and related pathogenic genes of osteopetrosis. Then we summarize and describe the characteristics of craniofacial and dental abnormalities in osteopetrosis that have been published in PubMed from 1965 to the present. We found that all 13 types of osteopetrosis have craniomaxillofacial and dental phenotypes. The main pathogenic genes, such as chloride channel 7 gene (CLCN7), T cell immune regulator 1 (TCIRG1), osteopetrosis-associated transmembrane protein 1 (OSTM1), pleckstrin homology domain-containing protein family member 1 (PLEKHM1), and carbonic anhydrase II (CA2), and their molecular mechanisms involved in craniofacial and dental phenotypes, are discussed. We conclude that the telltale craniofacial and dental abnormalities are important for dentists and other clinicians in the diagnosis of osteopetrosis and other genetic bone diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Craniofacial Birth Defects)
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