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PubMed1998

Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands.

The thymus, thyroid, and parathyroid glands in vertebrates develop from the pharyngeal region, with contributions both from pharyngeal endoderm and from neural crest cells in the pharyngeal arches. Hoxa3 mutant homozygotes have defects in the development of all three organs. Roles for the Hoxa3 paralogs, Hoxb3 and Hoxd3, were investigated by examining various mutant combinations. The thyroid defects seen in Hoxa3 single mutants are exacerbated in double mutants with either of its paralogs, although none of the double-mutant combinations resulted in thyroid agenesis. The results indicate that the primary role of these genes in thyroid development is their effect on the development and migration of the ultimobranchial bodies, which contribute the parafollicular or C-cells to the thyroid. Hoxb3, Hoxd3 double mutants show no obvious defects in the thymus or parathyroids. However, the removal of one functional copy of Hoxa3 from the Hoxb3, Hoxd3 double mutants (Hoxa3 +/-, Hoxb3-/-, Hoxd3-/-) results in the failure of the thymus and parathyroid glands to migrate to their normal positions in the throat. Very little is known about the molecular mechanisms used to mediate the movement of tissues during development. These results indicate that Hoxa3, Hoxb3, and Hoxd3 have highly overlapping functions in mediating the migration of pharyngeal organ primordia. In addition, Hoxa3 has a unique function with respect to its paralogs in thymus, parathyroid, and thyroid development. This unique function may be conferred by the expression of Hoxa3, but not Hoxb3 nor Hoxd3, in the pharyngeal pouch endoderm.

Animals↗
PubMed2002

[Effects of the mutant gene wellhaarig in chimeric mice].

The mutant gene wellhaaring (we) confers the waved coat in mice, which is most pronounced in homozygotes at 10 to 21 days of postnatal development. Abnormal hair growth and structure in the we/we mutant mice results from defective cell differentiation in the inner root sheath of a hair follicle. To localize the site of the we gene action, we obtained ten chimeric mice by aggregation of the early C57BL/6-2we/we and BALB/c embryos. The chimera coat was waved, shaggy, or almost normal depending on the percentage of the mutant component. In the we/we +/+ chimeric animals of the first generation (G1) aged 21 days, both mutant and normal hair phenotypes were observed, which was especially discernible in zigzag hair. Note that none of the chimeras exhibited the alternating patterns of transversely oriented stripes or patches of either mutant or normal hair; i.e., they had a mixed parental hair phenotype. We also did not observe the animals with an intermediate phenotype, which suggests a discontinuous hair formation in chimeras according to the "all or nothing" principle. The data obtained indicate that the dermal papilla cells of a hair follicle are the sites for the we gene action. During the embryonic development, dermal cells are strongly mixed, which accounts for the lack of the clear-cut transverse stripes of either mutant or normal hair. The mutant gene we is probably responsible for a disrupted induction signal from the dermal papilla towards ectodermal cells of a hair follicle.

Animals↗
PubMed1992

Mechanism of anteroposterior axis specification in vertebrates. Lessons from the amphibians.

Interest in the problem of anteroposterior specification has quickened because of our near understanding of the mechanism in Drosophila and because of the homology of Antennapedia-like homeobox gene expression patterns in Drosophila and vertebrates. But vertebrates differ from Drosophila because of morphogenetic movements and interactions between tissue layers, both intimately associated with anteroposterior specification. The purpose of this article is to review classical findings and to enquire how far these have been confirmed, refuted or extended by modern work. The "pre-molecular" work suggests that there are several steps to the process: (i) Formation of anteroposterior pattern in mesoderm during gastrulation with posterior dominance. (ii) Regional specific induction of ectoderm to form neural plate. (iii) Reciprocal interactions from neural plate to mesoderm. (iv) Interactions within neural plate with posterior dominance. Unfortunately, almost all the observable markers are in the CNS rather than in the mesoderm where the initial specification is thought to occur. This has meant that the specification of the mesoderm has been assayed indirectly by transplantation methods such as the Einsteckung. New molecular markers now supplement morphological ones but they are still mainly in the CNS and not the mesoderm. A particular interest attaches to the genes of the Antp-like HOX clusters since these may not only be markers but actual coding factors for anteroposterior levels. We have a new understanding of mesoderm induction based on the discovery of activins and fibroblast growth factors (FGFs) as candidate inducing factors. These factors have later consequences for anteroposterior pattern with activin tending to induce anterior, and FGF posterior structures. Recent work on neural induction has implicated cAMP and protein kinase C (PKC) as elements of the signal transduction pathway and has provided new evidence for the importance of tangential neural induction. The regional specificity of neural induction has been reinvestigated using molecular markers and provides conclusions rather similar to the classical work. Defects in the axial pattern may be produced by retinoic acid but it remains unclear whether its effects are truly coordinate ones or are concentrated in certain regions of high sensitivity. In general the molecular studies have supported and reinforced the "pre-molecular ones". Important questions still remain: (i) How much pattern is there in the mesoderm (how many states?) (ii) How is this pattern generated by the invaginating organizer? (iii) Is there one-to-one transmission of codings to the neural plate? (iv) What is the nature of the interactions within the neural plate? (v) Are the HOX cluster genes really the anteroposterior codings?

Animals↗
PubMed1985

The effect of syndrome diagnosis on speech remediation.

On the basis of work reported by colleagues, as well as our own clinical research studies of patients with the aforementioned syndromes, there are now some useful guidelines for appropriate remediation based on accurate initial diagnosis. Still, there is more to be learned about each of these syndromes. Furthermore, they represent but a small sample of a very large total. Recent literature has described the speech patterns of many more syndromes, as well as the genetic aspects of the more common speech and language disorders such as language delay, dyslexia, autism, and stuttering [72-78]. The most common recognizable birth defect is Down syndrome and there is, fortunately, a large body of information detailing the varied language, speech, and hearing aspects [79]. Those of us who work with children with Down syndrome have been alerted to the anticipated receptive and expressive language delays; the conductive and sometimes mixed hearing losses; the hoarse and raucous voices that are probably the result of a combination of anatomic, neurologic, and mucosal variations; the interesting disfluencies, and the amalgam of developmental and deviant articulatory errors. We know that although the tongue protrudes, it is rarely the true macroglossia which we would find in Beckwith syndrome, for example, but rather a hypotonic posture and a logical adaptation to an airway restricted by enlarged tonsils and adenoids and recurrent rhinitis.

Abnormalities, Multiple↗
PubMed2004

Cdx2 is essential for axial elongation in mouse development.

Inactivation of Cdx2 leads to preimplantation embryonic lethality. Rescue of the implantation defect by tetraploid fusion established that Cdx2 is necessary for trophoblastic development, vasculogenesis in the yolk sac mesoderm, allantoic growth, and chorioallantoic fusion. "Rescued" Cdx2 mutants die at late gastrulation stages because of failure of placental development. Cdx2 is also needed for the completion of the normal process of gastrulation and tail bud elongation. Presegmental paraxial mesoderm is severely restricted in amount and somites posterior to somite 5 are abnormal. The Cdx2 mutation, like mutations impairing Wnt and Fgf signaling, causes posterior truncations and disturbs axial patterning of the embryonic structures, indicated by changes in the Hox expression domains. The gene appears to be important in the integration of the pathways controlling embryonic axial elongation, and anterior-posterior patterning.

Animals↗
PubMed1999

Regulation of neural crest cell populations: occurrence, distribution and underlying mechanisms.

Regulation is a significant developmental event because successful cell proliferation and migration are critical to shaping young embryos. Regulation -- the replacement of undifferentiated embryonic cells by other cells in response to signals received from the environment -- is distinct from wound healing and regeneration. Investigations on regulation of neural crest cells span all vertebrates and have revealed that regulative ability varies both among classes (even species), and spatially and temporally within individuals. In general, there is greatest regulation for cranial neural crest cells, less for trunk, and virtually none forcardiac. Regulation also appears to be more complete at early embryonic stages. Fate-mapping studies have demonstrated that large regions of neural crest cells must be removed to generate missing or morphologically reduced structures. Recent studies reveal that less extensive neural crest cell extirpations result in normal morphology of cartilaginous and neuronal elements in the head, and normal development of pigmentation in the trunk. Ablation of cardiac neural crest cells frequently generates abnormalities of the heart, great vessels and parasympathetic nerve innervation. Decreased cell death, increased division, change in fate and altered migration are possible cellular mechanisms of regulation. In mostcases, the specific mechanisms of regulation are unknown, but a major premise underlying regulation is that cell potential is greater than cell fate. This concept was born from studies which demonstrated that some cells were able to express alternative fates if transplanted to a new environment. Among the potential cellular mechanisms for regulation, cell migration has received the most attention. Following ablation of neural crest cells, replacement neural crest cells migrate into gaps, most frequently from anterior/posterior locations. Cells from surrounding epidermal and neural ectoderm may have limited regulative ability, while compensation by cells from the ventral neural tube has been demonstrated to an even lesser extent. Regulation by such non-crest cells would require their transformation into neural crest cells. The potential for regulation of neural crest by placodal cells supports a closer relationship between neural crest and placodal ectoderm than previously recognized. Decreased cell death has been discussed primarily with reference to (1) cranial ganglia that have dual contributions from neural crest and placodal cells and (2) programmed cell death in rhombomeres three and five. Increased cell division in response to neural crest ablation is likely more common than has been reported, but this mechanism is difficult to interpret without a 3-D context for viewing how patterns of division differ from normal. Lastly, changes in cell fate may be the driving factor in regulation of embryonic cells. It has been repeatedly demonstrated thatcell potential is greaterthan cell fate. Once reliable mechanisms for assessing cell potential are established, we may find that fates are commonly altered in response to environmental signals. Regulation is therefore significant both as a basic developmental mechanism and as a mechanism for evolutionary change. The more labile the fate of embryonic cells, the more potential there is for maintaining existing characters and for generating new ones. According to Ettensohn (1992, p. 50), further analysis of such systems might < >. With regard to the neural crest, studies on regulation of this vital population of cells provide insight to the origin of the neural crest, to embryonic repair, and to the source of many craniofacial malformations, heart and other embryonic defects. (ABSTRACT TRUNCATED)

Animals↗
PubMed1996

Embryonic mesoderm cells spread in response to platelet-derived growth factor and signaling by phosphatidylinositol 3-kinase.

Abnormal mesoderm movement, leading to defects in axial organization, is observed in mouse and Xenopus laevis embryos deprived of platelet-derived growth factor (PDGF) AA signaling. However, neither the cellular response to PDGF nor the signaling pathways involved are understood. Herein we describe an in vitro assay to examine the direct effect of PDGF AA on aggregates of Xenopus embryonic mesoderm cells. We find that PDGF AA stimulates aggregates to spread on fibronectin. This behavior is similar to that of migrating mesoderm cells in vivo that spread and form lamellipodia and filipodia on contact with fibronectin-rich extracellular matrix. We go on to show two lines of evidence that implicate phosphatidylinositol 3-kinase (PI3K) as an important component of PDGF-induced mesoderm cell spreading. (i) The fungal metabolite wortmannin, which inhibits signaling by PI3K, blocks mesoderm spreading in response to PDGF AA. (ii) Activation of a series of receptors with specific tyrosine-to-phenylalanine mutations revealed PDGF-induced spreading of mesoderm cells depends on PI3K but not on other signaling molecules that interact with PDGF receptors including phospholipase C gamma, Ras GTPase-activating protein, and phosphotyrosine phosphatase SHPTP2. These results indicate that a PDGF signal, medicated by PI3K, can facilitate embryonic mesoderm cell spreading on fibronectin. We propose that PDGF, produced by the ectoderm, influences the adhesive properties of the adjacent mesoderm cells during gastrulation.

Androstadienes↗
PubMed1997

Acute lymphoblastic leukemia in a child with the CHIME neuroectodermal dysplasia syndrome.

The "CHIME" syndrome (MIM#280000) is a rare neuroectodermal disorder comprised of Colobomas of the eye, Heart defects, Ichthyosiform dermatosis, Mental retardation, and Ear defects. We report on the sixth child with this syndrome and the first of these to develop acute lymphoblastic leukemia at age 4 1/2 years. Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss. Histologic examination of the skin demonstrated findings of an epidermal nevus with deep rete pegs, hyperkeratosis, and a markedly increased granular layer. The cause of the CHIME syndrome is unknown, but the disorder is easily recognized because of the striking phenotype. The diagnosis is important to make because of the potential for associated congenital heart disease, neurologic compromise, possible autosomal recessive inheritance, and possible association with malignancy.

Child, Preschool↗
PubMed1996

shotgun encodes Drosophila E-cadherin and is preferentially required during cell rearrangement in the neurectoderm and other morphogenetically active epithelia.

Adhesion molecules of the cadherin superfamily have an important role during vertebrate development. The DE-cadherin homolog DE-cadherin is the first classic cadherin isolated from invertebrates. We report here that DE-cadherin is encoded by the shotgun (shg) gene. shg is expressed in most embryonic epithelia and decreases in cells that undergo epithelial-mesenchymal transitions like the mesoderm or neural precursors. Removal of both maternal and zygotic shg function leads to severe defects in all epithelia expressing shg, suggesting that DE-cadherin, similar to vertebrate classic cadherins, has a crucial role for the formation and/or maintenance of epithelial tissues. Interestingly, the analysis of different shg alleles indicates that the requirement for shg in a given epithelium depends on the degree of its morphogenetic activity. Only epithelia involved in extensive morphogenetic movements require zygotic shg function in addition to maternal expression. In support of this view we find that suppression of morphogenetic movements rescues the zygotic shg phenotype. We find that in zygotic shg nulls the level of Dalpha-catenin and Armadillo at adherens junctions is dramatically reduced, surprisingly also in epithelia that differentiate normally and possess a zonula adherens.

Animals↗
PubMed2002

A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan.

Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

Adult↗
PubMed1992

Lens structures exist transiently in development of transgenic mice carrying an alpha-crystallin-diphtheria toxin hybrid gene.

The development of lens structures in transgenic mice (lnl mice) which carry the diphtheria toxin A chain-coding sequence under the control of the alpha-crystallin promoter is examined here in detail. The initial stages of lens development during embryonic days 10.5 to 12.5 (E10.5-E12.5), including the invagination of the surface ectoderm to form a lens vesicle, closure of the vesicle to form a lens cup, and initial appearance of the lens itself, appeared identical in histologic analyses of lnl mice and genotypically wild-type littermate controls. However, by E12.5, cells in the central posterior lens of developing lnl mice appeared to be vacuolated and undergoing necrosis. This necrosis was quite prominent at E14.5 and the overall lens size was significantly reduced. The lenses of lnl mice continued to be present but were significantly smaller throughout embryonic development. The cells of these lenses were capable of undergoing biochemical differentiation, reacting with antibodies to both alpha- and beta-/gamma-crystallin. alpha-Crystallin expression was initiated at the appropriate time (E10.5) and maintained in most cells of lnl lenses. The expression of beta-/gamma-crystallins was surprising as these crystallins are expressed later in lens development after normal expression of alpha-crystallin and after the anticipated time of expression of the diphtheria toxin transgene. Despite extensive necrosis and cell death, lens structures persisted in lnl mice and disappeared only in the early postnatal period between days 3 and 6. Throughout the perinatal period, the remaining lens cells expressed both alpha- and beta-/gamma-crystallins. Prenatal development of the retina and ciliary body was relatively normal although the eye was significantly reduced in overall size. Some additional developmental defects were noted including persistent hyaloid artery and thickened cornea. In the perinatal period the rapidly expanding retina filled the entire eye leaving essentially no anterior or posterior chamber. These results clearly indicate that lens cells which are the target of diphtheria toxin-mediated cell ablation techniques persist for a significant time during development and thus place limitations on the interpretations of results obtained using this technique.

Animals↗
PubMed2006

Recent advances in craniofacial morphogenesis.

Craniofacial malformations are involved in three fourths of all congenital birth defects in humans, affecting the development of head, face, or neck. Tremendous progress in the study of craniofacial development has been made that places this field at the forefront of biomedical research. A concerted effort among evolutionary and developmental biologists, human geneticists, and tissue engineers has revealed important information on the molecular mechanisms that are crucial for the patterning and formation of craniofacial structures. Here, we highlight recent advances in our understanding of evo-devo as it relates to craniofacial morphogenesis, fate determination of cranial neural crest cells, and specific signaling pathways in regulating tissue-tissue interactions during patterning of craniofacial apparatus and the morphogenesis of tooth, mandible, and palate. Together, these findings will be beneficial for the understanding, treatment, and prevention of human congenital malformations and establish the foundation for craniofacial tissue regeneration.

Animals↗
PubMed1991

The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily.

Recessive lethal mutations in the fat locus of Drosophila cause hyperplastic, tumor-like overgrowth of larval imaginal discs, defects in differentiation and morphogenesis, and death during the pupal stage. Clones of mutant cells induced by mitotic recombination demonstrate that the overgrowth phenotype is cell autonomous. Here we show that the fat locus encodes a novel member of the cadherin gene superfamily: an enormous transmembrane protein of over 5000 amino acids with a putative signal sequence, 34 tandem cadherin domains, four EGF-like repeats, a transmembrane domain, and a novel cytoplasmic domain. Two recessive lethal alleles contain alterations in the fat coding sequence, and the dominant fat allele, Gull, contains an insertion of a transposable element in the 33rd cadherin domain. Thus, this novel member of the cadherin gene superfamily functions as a tumor suppressor gene and is required for correct morphogenesis.

Alleles↗
PubMed2003

The zinc-finger protein CNBP is required for forebrain formation in the mouse.

Mouse mutants have allowed us to gain significant insight into axis development. However, much remains to be learned about the cellular and molecular basis of early forebrain patterning. We describe a lethal mutation mouse strain generated using promoter-trap mutagenesis. The mutants exhibit severe forebrain truncation in homozygous mouse embryos and various craniofacial defects in heterozygotes. We show that the defects are caused by disruption of the gene encoding cellular nucleic acid binding protein (CNBP); Cnbp transgenic mice were able to rescue fully the mutant phenotype. Cnbp is first expressed in the anterior visceral endoderm (AVE) and, subsequently, in the anterior definitive endoderm (ADE), anterior neuroectoderm (ANE), anterior mesendoderm (AME), headfolds and forebrain. In Cnbp(-/-) embryos, the visceral endoderm remains in the distal tip of the conceptus and the ADE fails to form, whereas the node and notochord form normally. A substantial reduction in cell proliferation was observed in the anterior regions of Cnbp(-/-) embryos at gastrulation and neural-fold stages. In these regions, Myc expression was absent, indicating CNBP targets Myc in rostral head formation. Our findings demonstrate that Cnbp is essential for the forebrain induction and specification.

Animals↗
PubMed2005

Restoring DNA repair capacity of cells from three distinct diseases by XPD gene-recombinant adenovirus.

The nucleotide excision repair (NER) is one of the major human DNA repair pathways. Defects in one of the proteins that act in this system result in three distinct autosomal recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). TFIIH is a nine-protein complex essential for NER activity, initiation of RNA polymerase II transcription and with a possible role in cell cycle regulation. XPD is part of the TFIIH complex and has a helicase function, unwinding the DNA in the 5' --> 3' direction. Mutations in the XPD gene are found in XP, TTD and XP/CS patients, the latter exhibiting both XP and CS symptoms. Correction of DNA repair defects of these cells by transducing the complementing wild-type gene is one potential strategy for helping these patients. Over the last years, adenovirus vectors have been largely used in gene delivering because of their efficient transduction, high titer, and stability. In this work, we present the construction of a recombinant adenovirus carrying the XPD gene, which is coexpressed with the EGFP reporter gene by an IRES sequence, making it easier to follow cell infection. Infection by this recombinant adenovirus grants full correction of SV40-transformed and primary skin fibroblasts obtained from XP-D, TTD and XP/CS patients.

Adenoviridae↗
PubMed1997

Cloning of Tabby, the murine homolog of the human EDA gene: evidence for a membrane-associated protein with a short collagenous domain.

X-Linked hypohidrotic ectodermal dysplasia (XLHED) is a human congenital disorder resulting in abnormal tooth, hair and sweat gland development. A candidate gene for the disorder has been cloned, but the function and full size of its putative protein product is unclear. We have identified a candidate cDNA for the mouse Tabby gene (Ta), which, based on phenotype and syntenic mapping, is postulated to represent the analogous murine disorder. Mutations have been identified in three different Ta alleles and Northern analysis indicates that the gene is expressed at increasing levels during embryogenesis (11-17 days p.c.), the period when affected structures develop. The putative protein product encoded by exon 1 is highly homologous (87% identical) to the predicted EDA protein product (135 amino acids), including the presence of a single transmembrane domain. However, the murine cDNA also encodes an additional 246 amino acids, which contains a short collagenous domain (Gly-X-Y)19. This predicted structure is similar to a number of membrane-associated proteins with either single or multiple collagenous domains in their extracellular C-terminal regions. Since mutations can only be identified in 10-15% of families with XLHED, it is likely that additional homologous exons exist for the human EDA gene. Hybridization of YACs from the EDA region with the Ta cDNA support this hypothesis. The predicted extracellular collagenous domain of this membrane protein may play a key role in epithelial-mesenchymal interactions, defects of which are thought to underlie the Ta/XLHED phenotype.

Amino Acid Sequence↗
PubMed2001

Hmx2 homeobox gene control of murine vestibular morphogenesis.

Development of the vertebrate inner ear is characterized by a series of genetically programmed events involving induction of surface ectoderm, preliminary morphogenesis, specification and commitment of sensory, nonsensory and neuronal cells, as well as outgrowth and restructuring of the otocyst to form a complex labyrinth. Hmx2, a member of the Hmx homeobox gene family, is coexpressed with Hmx3 in the dorsolateral otic epithelium. Targeted disruption of Hmx2 in mice demonstrates the temporal and spatial involvement of Hmx2 in the embryonic transition of the dorsal portion (pars superior) of the otocyst to a fully developed vestibular system. In Hmx2 null embryos, a perturbation in cell fate determination in the lateral aspect of the otic epithelium results in reduced cell proliferation in epithelial cells, which includes the vestibular sensory patches and semicircular duct fusion plates, as well as in the adjacent mesenchyme. Consequently, enlargement and morphogenesis of the pars superior of the otocyst to form a complex labyrinth of cavities and ducts is blocked, as indicated by the lack of any distinguishable semicircular ducts, persistence of the primordial vestibular diverticula, significant loss in the three cristae and the macula utriculus, and a fused utriculosaccular chamber. The developmental regulators Bmp4, Dlx5 and Pax2 all play a critical role in inner ear ontogeny, and the expression of each of these genes is affected in the Hmx2 null otocyst suggesting a complex regulatory role for Hmx2 in this genetic cascade. Both Hmx2 and Hmx3 transcripts are coexpressed in the developing central nervous system including the neural tube and hypothalamus. A lack of defects in the CNS, coupled with the fact that not all of the Hmx2-positive regions in developing inner ear are impaired in the Hmx2 null mice, suggest that Hmx2 and Hmx3 have both unique and overlapping functions during embryogenesis.

Animals↗
PubMed2000

Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia.

Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive. Approximately 70% of CL/P cases are non-syndromic (MIM 119530), but CL/P also occurs in many single-gene syndromes, each affecting a protein critical for orofacial development. Here we describe positional cloning of the gene responsible for an autosomal recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (HveC; ref. 7), and the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might result from resistance of heterozygotes to infection by these viruses.

Amino Acid Sequence↗