Sachiko Iseki

• Tokyo Medical and Dental University

Sonic hedgehog ( Shh ) is expressed in the oropharyngeal epithelium, including the frontonasal ectodermal zone (FEZ), which is defined as the boundary between Shh and Fgf8 expression domains in the frontonasal epithelium. To investigate the role of SHH signaling from the oropharyngeal epithelium, we generated mice in which Shh expression is specifi...

Background Mutations in genes encoding spliceosome components result in craniofacial structural defects in humans, referred to as spliceosomopathies. The SF3b complex is a crucial unit of the spliceosome, but model organisms generated through genetic modification of the complex do not perfectly mimic the phenotype of spliceosomopathies. Since the p...

The renal glomerulus produces primary urine from blood plasma by ultrafiltration. The ultrastructure of the glomerulus is closely related to filtration function and disease development. The ultrastructure of the glomeruli has mainly been evaluated using transmission electron microscopy. However, the volume that can be observed using transmission el...

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells that are directly involved in development, homeostasis and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial bone repair, neural crest cells have been proposed to be key players; however, neural cre...

Background The hyolaryngeal apparatus generates biosonar pulses in the laryngeally echolocating bats. The cartilage and muscles comprising the hyolarynx of laryngeally echolocating bats are morphologically modified compared to those of non-bat mammals, as represented by the hypertrophied intrinsic laryngeal muscle. Despite its crucial contribution...

Fibroblast growth factor (FGF) signalling plays a crucial role in the morphogenesis of multiple tissues including teeth. While the role of the signal has been studied in tooth crown development, little is known about root development. Of several FGF ligands involved in hard tissue formation, we suggest that FGF18 regulates the development of murine...

Background The hyolaryngeal apparatus generates biosonar pulses in the laryngeally echolocating bats. The cartilage and muscles comprising the hyolarynx of laryngeally echolocating bats are morphologically modified compared to those of non-bat mammals, as represented by the hypertrophied intrinsic laryngeal muscle. Despite its crucial contribution...

Fibroblast growth factor (FGF) signaling plays essential roles in various biological events. FGF18 is one of the ligands to be associated with osteogenesis, chondrogenesis and bone healing. The mouse critical-sized calvarial defect healing induced by the bone morphogenetic protein 2 (BMP2)-hydrogel is stabilized when FGF18 is added. Here, we aimed...

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells (SSCs) that are directly involved in development, homeostasis, and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial repair, neural crest cells have been proposed to be key players; however, neural...

Objective: To investigate whether there is a difference in apical resorption activity during the development of roots in response to mechanical force in vivo. Methods: Maxillary first molars (M1) from postnatal day (PN) 21 and PN35 male rats were selected as representatives of the root-developing and root-completing groups, respectively. A mecha...

Engineered cartilage tissue from differentiated mesenchymal stem cells (MSCs) can generate bone in vivo through endochondral ossification (ECO). This ECO-mediated approach has the potential to circumvent the severe problems associated with conventional MSC-based bone tissue engineering techniques that lack mechanisms to induce angiogenesis. Hyaluro...

Bats have undergone one of the most drastic limb innovations in vertebrate history, associated with the evolution of powered flight. Knowledge of the genetic basis of limb organogenesis in bats has increased but little has been documented regarding the differences between limb organogenesis in bats and that of other vertebrates. We conducted embryo...

Introduction: The suitable timing and duration of orthodontic force to be applied to teeth with developing roots are unclear. We investigated the effects of short-term orthodontic force application on the roots at different root developmental stages in rats to predict the optimal timing for orthodontic treatment of teeth with developing roots. Me...

Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this study, we chronologically evaluated skull morphology change after abnormal fusion of the sutures and synchondroses in mouse models of syndromic CS for further understanding of the disea...

The histone methyltransferase SET domain bifurcated 1 (SETDB1) catalyzes the trimethylation of lysine 9 of histone H3, thereby regulating gene expression. In this study, we used conditional knockout mice, where Setdb1 was deleted only in neural crest cells (Setdb1 fl/fl, Wnt1-Cre + mice), to clarify the role of SETDB1 in palatal development. Setdb1...

Background: The haploinsufficiency in the TWIST1 gene encoding a basic helix-loop-helix transcription factor is a cause of one of the craniosynostosis syndromes, Saethre-Chotzen syndrome. Patients with craniosynostosis usually require operative release of affected sutures, which makes it difficult to observe the long-term consequence of suture fus...

Background The vertebrate tongue is a complex muscular organ involved in mastication, taste sensation, and articulation. The tongue is affected in many syndromes, diseases, and malignancies. It has recently been shown that a cascade of signaling interactions between different cell populations during embryogenesis orchestrates the development of the...

Bone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding of the mechanisms that regulate bone formation. Here, we discover a previo...

Background Foxc2 is a member of the winged helix/forkhead (Fox) box family of transcription factors. Loss of function of Foxc2 causes craniofacial abnormalities such as cleft palate and deformed cranial base, but its role during craniofacial development remains to be elucidated. Results The contributions of Foxc2‐positive and its descendant cells...

The AT‑rich interacting domain (ARID) family of DNA‑binding proteins is involved in various biological processes, including the regulation of gene expression during cell proliferation, differentiation and development. ARID3A and ARID3B are involved in chromatin remodeling and can bind to E2F1 and retinoblastoma tumor suppressor protein (RB), respec...

Neural crest cells (NCCs) give rise to various tissues including neurons, pigment cells, bone and cartilage in the head. Distal-less homeobox 5 (Dlx5) is involved in both jaw patterning and differentiation of NCC-derivatives. In this study, we investigated the differentiation potential of head mesenchyme by forcing Dlx5 to be expressed in mouse NCC...

The field of tissue engineering and regeneration constantly explores the possibility of utilizing various biomaterials’ properties to achieve effective and uneventful tissue repairs. Polyrotaxanes (PRXs) are supramolecular assemblies, which possess interesting mechanical property at a molecular scale termed as molecular mobility. This molecular mob...

Cover illustration : The cover image is based on the Short Communication Conditional Inactivation of Foxc1 and Foxc2 in Neural Crest Cells Leads to Cardiac Abnormalities by Tsutomu Kume, Ting Liu, Risa Miyake et al.,https://doi.org/10.1002/dvg.23364.

During palatogenesis, the palatal shelves first grow vertically on either side of the tongue before changing their direction of growth to horizontal. The extracellular matrix (ECM) plays an important role in these dynamic changes in palatal shelf morphology. Tenascin-C (TNC) is an ECM glycoprotein that shows unique expression in the posterior part...

Cardiac neural crest cells (cNCCs) are required for normal heart development. cNCCs are a multipotent and migratory cell lineage that differentiates into multiple cell types. cNCCs migrate into the developing heart to contribute to the septation of the cardiac outflow tract (OFT). Foxc1 and Foxc2 are closely related members of the FOX (Forkhead box...

There exists a close connection between changes occurring in the teeth and those occurring in the jaw during the evolutionary process. In mammals, the roots of teeth are supported, along with periodontal ligaments and alveolar bones by a unique structure termed the gomphosis. In the present study, we performed combined in silico analysis using the...

Background Splicing factor 3B subunit 4 (SF3B4) is a causative gene of an acrofacial dysostosis, Nager syndrome. Although in vitro analyses of SF3B4 have proposed multiple noncanonical functions unrelated to splicing, less information is available based on in vivo studies using model animals. Results We performed expression and functional analyses...

AT-rich interacting domain 3B (ARID3B) is a component of a chromatin remodeling complex, and overexpressed in malignant tumors. ARID3B forms a heterodimer with closely related ARID3A, which has been isolated as a protein binding to the E2F1 transcription factor. In this study, we found putative ARID3-binding sites in promotors or introns of E2F-res...

The tongue is a highly specialised muscular organ with a complex anatomy required for normal function. We have utilised multiple genetic approaches to investigate local temporospatial requirements for sonic hedgehog (SHH) signalling during tongue development. Mice lacking a Shh cis-enhancer, MFCS4 (ShhMFCS4/-), with reduced SHH in dorsal tongue epi...

Objectives: We aimed to investigate the effects of mechanical force application on the developing root apex in vivo. Design: Mechanical force was applied on the maxillary first molars of Sprague-Dawley rats at postnatal day 21 for 1, 3, 5, and 7 days to induce tooth movement. We observed the developing root apex of the mesial root of first molar...

Human mesenchymal stem cells (hMSCs) are prone to senescence and lose their differentiation potential when expanded under nonfavorable conditions. This leads to the underutilization of hMSCs in clinical situations such as bone regeneration. The use of growth factors and small molecules as supplements and changing the physical properties of the cell...

The vertebrate tongue is a complex muscular organ situated in the oral cavity and involved in multiple functions including mastication, taste sensation, articulation and the maintenance of oral health. Although the gross embryological contributions to tongue formation have been known for many years, it is only relatively recently that the molecular...

The cranial base is a structure mainly formed through endochondral ossification, and integrated into the craniofacial complex acting as an underlying platform for developing brain. Foxc1 is an indispensable regulator during intramembranous and endochondral ossification. In this study, we found that the spontaneous loss of Foxc1 function mouse (cong...

Labial grooves in maxillary incisors have been reported in several wild-type rodent species. Previous studies have reported age-dependent labial grooves occur in moderate prevalence in C57BL/6 mice; however, very little is known about the occurrence of such grooves. In the present study, we observed age-dependent groove formation in C57BL/6 mice up...

Tooth and bone are major tissues involved in physiological calcification in the body, and they use similar molecular pathways for development, homeostasis, and regeneration. Harmine (HMN) is a natural small compound that stimulates osteoblast differentiation in vitro and in vivo. Here we examined the biological effect of HMN on the postnatal develo...

Bitter taste avoidance behavior (BAB) plays a fundamental role in the avoidance of toxic substances with a bitter taste. However, the molecular basis underlying the development of BAB is unknown. To study critical developmental events by which taste buds turn into functional organs with BAB, we investigated the early phase development of BAB in pos...

For craniofacial bone regeneration, shear thinning injectable hydrogels are favoured over conventional scaffolds due to their improved defect margin adaptability, easier handling and ability to be injected manually into deeper tissues. The most accepted method, after autografting, is the use of recombinant human BMP-2; however, complications such a...

We have proposed that independent origins of the tympanic membrane (TM), consisting of the external auditory meatus (EAM) and first pharyngeal pouch, are linked with distinctive middle ear structures in terms of dorsal-ventral patterning of the pharyngeal arches during amniote evolution. However, previous studies have suggested that the first phary...

Bone is a metabolically active organ that undergoes continuous remodeling throughout life. However, many complex skeletal defects such as large traumatic bone defects or extensive bone loss after tumor resection may cause failure of bone healing. Effective therapies for these conditions typically employ combinations of cells, scaffolds, and bioacti...

The tongue is a highly specialized muscular organ important for breathing, speech, taste and swallowing. The secreted signaling molecule Sonic hedgehog (Shh) is expressed in dorsal tongue epithelium from the initial developmental stage. In this study, we utilized a series of genetic approaches to investigate the role of Shh during mouse tongue form...

Objective Excess treatment of 13-cis-RA (Accutane®) on pregnant women induces craniofacial malformation found in infants. However, the effect of folic acid on 13-cis-RA-induced cellular damages of developing midfacial processes is still unknown. The purpose of this study was to investigate the pretreatment effect of folic acid (FA) on 13-cis-RA-ind...

A patient who had ectrodactyly, dry skin, exfoliative dermatitis, and hypodontia with peg-shaped teeth, but not cleft lip and palate, is described. Ectrodactyly with a tooth anomaly is recognized in both acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome. These 2 syndromes are caused by he...

Background Periventricular leukomalacia (PVL) is a type of multifactorial brain injury that causes cerebral palsy in premature infants. To date, effective therapies for PVL have not been available. In this study, we examined whether mesenchymal stem cells (MSCs) possess neuroprotective property in a lipopolysaccharide (LPS)-induced neonatal rat PVL...

Foxc2, a member of the winged helix transcription factor family, is essential for eye, calvarial bone, cardiovascular and kidney development in mice. Nevertheless, how Foxc2-expressing cells and their descendent cells contribute to the development of these tissues and organs has not been elucidated. Here, we generated a Foxc2 knock-in (Foxc2(CreERT...

Objective: The aim of this study was to establish a novel rat model of neonatal complications secondary to intra-amniotic infection/inflammation in order to investigate the therapeutic efficacy of rat umbilical cord-derived mesenchymal stem cells (rUCMSCs).Methods: On gestational age day (GAD) 16, approximately 0.2 μg of lipopolysaccharide (LPS) wa...

ARID3A and ARID3B are transcriptional targets of p53. Recently, it has been reported that ARID3A plays a critical role in the transcriptional activation of pro-arrest p21 in response to DNA damage. However, the role of ARID3B in the p53 regulatory pathway remains poorly understood. Here we show that ARID3A and ARID3B specifically bind to putative A...

The tympanic membrane is a thin layer that originates from the ectoderm, endoderm, and mesenchyme. Molecular-genetic investigations have revealed that interaction between epithelial and mesenchymal cells in the pharyngeal arches is essential for development of the tympanic membrane. We have recently reported that developmental mechanisms underlying...

Injectable gel systems, for the purpose of bone defect reconstruction has more advantages like controlled flowability, adaptability to the defect site, increased handling properties when compared to the conventionally used autologous graft, scaffolds, hydroxyapatite blocks etc. In this work, nano hydroxyapatite (nHAp) incorporated chitin-poly (ε-ca...

Indian hedgehog (Ihh) regulates endochondral ossification in both a parathyroid hormone-related protein (PTHrP)-dependent and -independent manner by activating transcriptional mediator Gli2. However, the molecular mechanisms underlying these processes remain elusive. Here by using in vivo microarray analysis, we identify forkhead box C1 (Foxc1) as...

Background: The brain vascular system arises from the perineural vascular plexus (PNVP) which sprouts radially into the neuroepithelium and subsequently branches off laterally to form a secondary plexus in the subventricular zone (SVZ), the subventricular vascular plexus (SVP). The process of SVP formation remains to be fully elucidated. We investi...

The frontal and parietal bones form the major part of the calvarium and their primordia appear at the basolateral region of the head and grow apically. A spontaneous loss of Foxc1 function mutant mouse, congenital hydrocephalus (Foxc1(ch/ch) ), results in congenital hydrocephalus accompanied by defects in the apical part of the skull vault. We foun...

Fibroblast growth factor (FGF) signaling is involved in skeletal development. Among total 22 FGFs, it is suggested that FGF18 functions in promotion of osteoblast differentiation. In order to elucidate the mechanism of FGF18-dependent acceleration of osteogenesis, we implanted rhFGF18 soaked beads over mouse fetal coronal sutures using ex-utero sur...

Hes genes are required to maintain diverse progenitor cell populations during embryonic development. Loss of Hes1 results in a spectrum of malformations of pharyngeal endoderm-derived organs, including the ultimobranchial body (progenitor of C cells), parathyroid, thymus and thyroid glands, together with highly penetrant C-cell aplasia (81%) and pa...

Apert syndrome is characterized by craniosynostosis and syndactyly, and is predominantly caused by mutation of either S252W or P253W in the fibroblast growth factor receptor (FGFR) 2 gene. In this study, we characterized the effects of one of the mutations (S252W) using primary calvarial osteoblasts derived from transgenic mice, Ap-Tg and sAp-Tg, t...

Hes1 gene represses the expression of proneural basic helix-loop-helix (bHLH) factor Mash1, which is essential for the differentiation of the sympathetic ganglia and carotid body glomus cells. The sympathetic ganglia, carotid body, and common carotid artery in Wnt1-Cre/R26R double transgenic mice were intensely labeled by X-gal staining, i.e., the...

To create a drug delivery system that allows the controlled release of proteins, such as growth factors, over a long-term period, cholesteryl group- and acryloyl group-bearing pullulan (CHPOA) nanogels were aggregated to form fast-degradable hydrogels (CHPOA/hydrogels) by cross-linking with thiol-bearing polyethylene glycol. The gold standard of cl...

ARID3A/DRIL1/E2FBP1 and ARID3B/Bdp are members of AT rich interaction domain (ARID) family proteins, which share a highly conserved DNA-binding domain. ARID3A was originally isolated as an E2F1-binding protein and stimulates transcription mediated by E2F transcription factor, which plays a central role in regulating cell cycle progression. ARID3B h...

We hypothesized that gene expression in placenta and umbilical vessels are affected by intrauterine environment and some of the expression in umbilical vessels originating from the fetus could reflect fetal condition of these complicated pregnancies. Expression of angiogenesis-related factors and inflammatory cytokines were examined in placenta and...

Oshiro A, Iseki S, Miyauchi M, Terashima T, Kawaguchi Y, Ikeda Y, Shinomura T. Lipopolysaccharide induces rapid loss of follicular dendritic cell-secreted protein in the junctional epithelium. J Periodont Res 2012; 47: 689–694. © 2012 John Wiley & Sons A/S Background and Objective: We have previously reported that mRNA encoding follicular dendritic...

The upper lip is formed by the fusion of facial processes, a process in which many genetic and environmental factors are involved. Embryonic hypoxia is induced by uterine anemia and the administration of vasoconstrictors during pregnancy. To define the relationship between hypoxia and upper lip formation, hypoxic conditions were created in a whole...

The tooth root is one of the critical parts to maintain tooth function; however, the molecular mechanisms of root development remain unknown. We aimed to identify specific factors for root morphogenesis using a newly developed experimental system. Tentative cementoblasts and periodontal ligament cells from mouse mandibular molars were isolated usin...

The palate is the ceiling of the oral cavity that separates the nasal and oral cavities in mammals. Anterior two-thirds of the palate that has the bone and the rugae on the oral surface is the hard palate, and the posterior one-third of the palate lacks bone and is referred to as the soft palate. Palate development involves a sequential process of...

ARID3A/DRIL1/Bright is a family member of the AT rich interaction domain (ARID) DNA-binding proteins that are involved in diverse biological processes. We have reported that p53 activates ARID3A transcription, and ARID3A overexpression induces G1 arrest. However, the role of ARID3A in the p53 pathway remains unclear. Here, we show that ARID3A coope...

The p53 tumor suppressor protein plays key roles in protecting cells from tumorigenesis. Phosphorylation of p53 at Ser46 (p53Ser46) is considered to be a crucial modification regulating p53-mediated apoptosis. Because the activity of p53 is impaired in most human cancers, restoration of wild-type p53 (wt-p53) function by its gene transfer or by p53...

High-mobility group box-1 (HMGB1) protein acts as a transcription factor in the nucleus and also as a pro-inflammatory cytokine when released into extracellular fluids. The presence of higher levels of HMGB1 is reported in the gingival crevicular fluid from periodontal patients. Since the proliferation of bacteria within the periodontal pocket is c...

During palatogenesis, the palatal medial edge epithelium (MEE) forms the medial epithelial seam (MES) on adhesion of the opposing palatal shelves. The MES eventually disappears, leading to mesenchymal confluence of the palate and completion of palatogenesis. Failure of these processes results in cleft palate, one of the most common congenital anoma...

Objectives: The tooth root is one of the most critical parts that support the force of tribosphenic functions, however, even molecular mechanisms of the root development remains unknown. Although various studies on tooth regeneration have been carried out, the tooth root structure remains to be difficult to regenerate. The aim of this study is to i...

Many vision-threatening diseases are characterized by intraocular neovascularization, (e.g., proliferative diabetic retinopathy and age-related macular degeneration). Although a new therapy with anti-VEGF antibodies is being used to treat these intraocular neovascular disorders, the visual recovery is limited, mainly because of the remnants of fibr...

Chondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1(f/f) mice and alpha1(II...

Tooth morphogenesis is regulated by reciprocal interactions between the dental epithelium and odontogenic mesenchyme. As tooth roots are fundamental structures of the tooth support system, the morphology and functions of the roots are very important. However, basic information on the morphology of tooth root patterning and the molecular mechanism o...

Tenascin-W is a tenascin family member that forms part of a complex extracellular matrix, and previous studies have suggested its association with osteogenesis. In the present study we investigated the roles of tenascin-W in osteogenesis. We found that tenascin-W is expressed in osteoblasts at the edge of the developing bone domain prior to mineral...

Objectives: Although various experiments regarding tooth regeneration have been carried out, only tooth crown has been so far the target. There is no report about the regeneration of a complete tooth including the root. The tooth root is the most critical part that maintains the tooth function, however, the molecular mechanism of root development r...

The spontaneous dominant mouse mutant, Elbow knee synostosis (Eks), shows elbow and knee joint synosotsis, and premature fusion of cranial sutures. Here we identify a missense mutation in the Fgf9 gene that is responsible for the Eks mutation. Through investigation of the pathogenic mechanisms of joint and suture synostosis in Eks mice, we identify...

Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepatic developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When...

The transcription factor E2F, the main target of the RB tumor suppressor pathway, plays crucial roles not only in cell proliferation but also in tumor suppression. The cyclin-dependent kinase inhibitor p27(Kip1) gene, an upstream negative regulator of E2F, is induced by ectopically expressed E2F1 but not by normal growth stimulation that physiologi...

The vertebrate cranial base is a complex structure composed of bone, cartilage and other connective tissues underlying the brain; it is intimately connected with development of the face and cranial vault. Despite its central importance in craniofacial development, morphogenesis and tissue origins of the cranial base have not been studied in detail...

We have analysed the contributions of neural crest and mesoderm to mammalian craniofacial mesenchyme and its derivatives by cell lineage tracing experiments in mouse embryos, using the permanent genetic markers Wnt1-cre for neural crest and Mesp1-cre for mesoderm, combined with the Rosa26 reporter. At the end of neural crest cell migration (E9.5) t...

Loss of function of the mouse forkhead/winged helix transcription factor Foxc1 induces congenital hydrocephalus and impaired skull bone development due to failure of apical expansion of the bone. In this study we investigated meningeal development in the congenital hydrocephalus (ch) mouse with spontaneous loss of function mutant of Foxc1, around t...

Retinal pigment epithelium (RPE) cells play important roles in the visual system that supports neurosensory retina homeostasis. Connexin (Cx) 43-mediated gap-junctional intercellular communication (GJIC) participates in the regulation of retinal organogenesis, but much of the function of Cx43 on the differentiation of RPE cells is unclear. Here, we...

Mammals possess reduced ability to regenerate lost tissue, compared with other vertebrates, which can regenerate through differentiation of precursor cells or de-differentiation. Mammalian multinucleated myotube formation is a differentiation process, which arises from the fusion of mononucleated myoblasts and is thought to be an irreversible proce...

Studies of chick-quail chimeras have reported that avian ultimobranchial C cells originate from the neural crest. It has consequently been assumed, without much supporting evidence, that mammalian thyroid C cells also originate from the neural crest. To test this notion, we employed both Connexin43-lacZ and Wnt1-Cre/R26R transgenic mice, because th...