The subcortex of the egg and early dividing embryo contains a plethora of proteins important for early development. For example, maternal E-cadherin (encoded by Cdh1) is present in the cortex and is required for the adherence of early blastomeres. However, if the proximity of the blastomeres is assured by the zona pellucida, the dividing embryo can survive the absence of maternal E-cadherin and can undergo normal compaction at the morula stage because of the embryonic expression of paternal Cdh1 (De Vries et al., 2004). As noted above, the absence of MATER or FLOPED prevents the formation of the SCMC (Table 2), another subcortical complex, and embryos do not progress beyond cleavage-stage embryogenesis (Li et al., 2008a). Although FILIA also participates in the SCMC, its absence in genetically ablated mice has a less catastrophic phenotype (Table 2). Importantly, the absence of FILIA does not preclude the subcortical localization of other components of the SCMC, and Filia-null female mice have a ~50% decrease in fecundity rather than sterility. Ovulated eggs from Filia-null mice are fertilized, but cell cycle progression is delayed by 6-8 hours during cleavage-stage embryogenesis. This more subtle phenotype provides mechanistic insight into the role of the SCMC in ensuring the fidelity of chromosome segregation during preimplantation mouse development. A relatively high rate of aneuploidy in embryos derived from Filia-null females implicates FILIA (and, by extension, the SCMC) in normal spindle formation via a RHOA signaling pathway and in maintaining the integrity of the spindle assembly checkpoint (Zheng and Dean, 2009).
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The importance of imprinting in visceral endoderm function and embryonic development is underscored by studies on parthenogenones, embryos that contain only maternal DNA. In mouse chimeras derived from normal fertilized and parthenoge- netic embryos, parthenogenetic cells contribute to the embryo proper and extraembryonic mesoderm, but not to extraembryonic endoderm or trophectoderm-derived tissues (Thomson and Solter, 1988). Parthenogenetic embryos derived from activation of dip- loid mouse oocytes develop to mid-gestation and show variable phenotypes, suggesting arrest at different developmental stages (Varmusa et al., 1993; Sturm et al., 1994). In the least affected embryos, which undergo gastrulation and develop proper A-P and D-V patterning, visceral endoderm shows a loss of characteristic apical vacuolization. The majority of these embryos show a reduction in forebrain structures that may reflect impairment of early signaling by AVE. In more disorganized embryos, ectoderm develops into a folded epithelium and visceral endoderm consists of a mixture of squamous and columnar cells. No primitive streak is formed and mesoderm, which migrates in disorganized fashion through the epiblast, becomes necrotic. The lack of axial pattern- ing and embryonic/extraembryonic boundary in these embryos may result for the ectopic expression of early markers in disorga- nized visceral endoderm, similar to the phenotype of Crypto null embryos. Finally, in the most severe phenotypes, the whole epiblast is missing or reduced to a small core of ectodermal cells. These embryos develop extraembryonic tissue in the form of abundant parietal endoderm and giant cells encased in thick extracellular matrix with a complete lack of visceral endoderm (Sturm et al., 1994). The different phenotypes described above may well represent disruption in particular functions of visceral endoderm, ranging from nutrient uptake to induction of gastrula- tion and axial patterning.
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The investigation of the effects of gain or loss of gene activity on embryonic development and mesodermal differentiation has pro- vided significant insight into the function of the Twist gene. It also reveals that the translation of the transcriptional regulation to the control of morphogenesis and tissue differentiation requires the activation or repression of molecular pathways that are down- stream of, and/or interacting with, Twist. The identification of downstream factors is achieved by assessing whether the expres- sion of specific genes may be altered by ectopically expressing or over-expressing Twist, or by interference with Twist activity. The analysis has taken two different approaches: first, specific sets of genes that are known to be involved with tissue morphogenesis and differentiation may be examined for being candidates of the downstream genes affected by Twist expression; second, a ge- nome-wide screening without any predilection of the response of all the expressing genes to the alteration of Twist activity (Furlong et al., 2001). Neither approach, however, could distinguish be- tween direct target genes and genes that are secondarily regulated by Twist downstream factors, without additional validation of transcriptional interaction. Further elucidation of the differential transcriptional activity of wild type and Twist mutant embryonic tissues coupled with functional tests of the candidate genes is crucial for a proper understanding of the molecular pathways regulated by TWIST, and to ascertain whether this transcription factor acts primarily as a repressor or as an activator.
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usually for tumour removal, yet some months later some facial movement on that side is observed. Evaluation shows that facial movement (resembling a smile) occurs when the patient bites down on the back molars. If this movement was achieved by regeneration of the facial nerve, re-excision o f the area should cause facial paralysis again. However, cases have been reported where the recovery o f movement is unaffected (Martin and Helsper, 1957), and additionally in the same patient when the mandibular branch o f the trigeminal was anaesthetised to alleviate neuralgia pain, all recovered function in the facial musculature was lost. In more recent studies, this involuntary smiling reflex persisted even when a nerve blocker (Xylocaine) was injected into the ipsilateral or contralateral facial nerve, ruling out regrowth o f the ipsilateral facial nerve or cross innervation by the contralateral intact facial nerve (Cheney et al., 1997). Therefore the trigeminal nerve is thought to be synapsing onto muscles normally innervated by facial motor neurons, restoring function. These findings are of great interest for the development of new surgical techniques to enable trigeminal neo-neurotisation in facial muscle paralysis.
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Previous studies have reported that MEE cells undergo apoptosis (Cuervo et al., 2002; Cuervo and Covarrubias, 2004), and a recent study suggested that the apoptosis in palatal MEE cells is mediated by caspase 3 (Vaziri et al., 2005). To determine whether apoptosis is essential for palate fusion and seam degeneration during mouse development in vivo, we examined palate fusion in Apaf1 mutant mouse embryos. The mouse Apaf1 gene is the mouse homolog of the C. elegans CED-4 gene, which encodes a crucial component in the caspase-3-mediated apoptosis pathway (Green and Reed, 1998). Apaf1 mutant mouse embryos are deficient in caspase 3 activation and display enormous apoptotic defects during embryonic development (Green and Reed, 1998; Honarpour et al., 2000). Surprisingly, we found that complete palate fusion still occurs in the Apaf1 mutant embryos. Histological analysis showed that the Apaf1 mutant palate forms a normal MEE seam at E14.5 (Fig. 4D), which undergoes degeneration at E15.5 (n=14; Fig. 4E). At E16.5 (n=10), the mutant embryos form a continuous palate with no residual seam cells (Fig. 4F). Interestingly, the mutant palates at E15.5 often present an enlarged triangular area that presents with more
When removed from factors maintaining pluripotency, ESCs can differentiate into derivatives of mesoderm, endoderm, and ectoderm lineages in vitro. ESC differentiation into specific lineages is typically achieved using three established methods (Murry and Keller, 2008). Firstly, under low adherence culture conditions, mESCs aggregate and form three-dimensional embryoid bodies (EBs) which mimic early post-implantation mouse development (Doetschman et al., 1985; Martin and Evans, 1975). If EBs remain in suspension, they form cystic structures and spontaneously generate endoderm, blood islands, and myocardium (Doetschman et al., 1985). If EBs adhere to a substrate (e.g. gelatin), differentiated cells emerge from the EB and form morphologically identifiable derivatives of the three germ layers (e.g. myocardial cells, neural cells, glandular cells, skeletal/smooth muscle cells, etc.) (Doetschman et al., 1985; Martin and Evans, 1975). The three-dimensional aspect of EB formation allows for cell-cell interactions, promoting the differentiation of certain lineages. However, the signalling factors and cytokines generated in these structures are complex and may confound investigation into the role of certain signalling pathways in ESC differentiation. Another disadvantage of forming large EB aggregates is the disorganization of differentiating cells that emerge, which does not fully recapitulate early mouse postimplantation development or gastrulation. To overcome this, it was recently discovered that smaller aggregates of mESCs
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The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function ( Shh-Cre;Rosa26 CAG-loxpstoploxp-caBmprIa ) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function
Schematics of the key players of mDA neuron development. Regionalisation of the neural tube (hindbrain (hb) brown, midbrain (mb) pink) establishes midbrain tissue identity via the inductive signals of Shh and Fgf8, which arise from the noto- chord (grey circle) and the midbrain-hindbrain border (blue) respectively, combined with Otx2 expression. This interaction enables midbrain ventral midline cells to respond to the later expression of the mDA neuron determination gene Lmx1a. Spec- ification of the mDA neuronal identity occurs within the proliferative zone (grey) of the ventral midline. Here, Msx1 and Foxa2 promote generic neurogenesis via regulation of Ngn2 whilst Lmx1a, supported by Msx1, specifies mDA neuron cell fate. As these mDA neuron progenitors become postmitotic and enter the intermediate zone (yellow), they begin to express the pan neuronal marker Tuj1 and, subsequently, the DA neuron transmitter regulator, Nurr1. Lmx1b and Wnt1 positively control early Pitx3 expression in some Nurr1 + cells. The last stage in mDA neuronal differentiation proceeds as the Pitx3 + cells and the
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CF 1 females were killed at 12.5 days of gestation and the conceptuses were dissected to provide five samples: fetus, amnion, yolk sac meso- derm, yolk sac endoderm and placenta. The mesoderm and endoderm layers of the visceral yolk sac were separated as previously described (West and Flockhart, 1994). Briefly, the visceral yolk sacs were put into separate wells, of 16-well plates, containing trypsin/pancreatin solution (0.5 g trypsin and 2.5 g pancreatin in 100 ml phosphate buffered saline), at 4°C for approximately 3.5 hours (Levak-Svajger et al., 1969). They were then transferred to fresh M2 medium for at least 30 min. at 4 ° C and finally transferred to another dish of fresh M2 medium and dissected with watchmaker’s forceps. The whole conceptus was weighed, the fetus and placenta were each weighed separately, the crown/rump length was measured and the morphological index, based on an assessment of hind limb development (McLaren and Buehr, 1990; Palmer and Burgoyne, 1991), was recorded.
Striking radial stripes have been reported in the corneal epithe- lium of adult chimeras and X-inactivation mosaics carrying lacZ transgenes (Collinson et al ., 2002) and mosaic GFP transgenic mice (Nagasaki and Zhao, 2003). The stripes in the corneal epithelium were much more marked than those seen in the periphery of the RPE spanning, in some instances, the full radius of the cornea (Fig. 3), and arose after birth. At three-weeks, LacZ mosaics had a pattern of randomly orientated patches rather than stripes. Stripes only emerged at the periphery at around 5 weeks and reached the centre by about 8 weeks (Fig. 3). The corneal epithelium is maintained throughout adult life by stem-like cells (limbal stem cells - LSCs) which reside around the edge of the cornea and produce progeny that migrate centripetally to replace cells lost during normal life. The radial stripes in mosaics and chimeras reflect this centripetal migration of corneal epithelial cells, as was confirmed by an elegant time-lapse study of move- ment of groups of GFP-positive cells in mosaic GFP transgenic mice (Nagasaki and Zhao, 2003) (Fig. 4). It is now clear that development of the corneal epithelium produces randomly orien- tated patches of cells in neonates which are subsequently re- placed by cells derived from LSCs at the periphery of the cornea.
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The interfollicular epidermis can essentially be divided into three basic compartments. The basal epidermis where the prolif- eration occurs, the suprabasal epidermis, containing post-mitotic keratinocytes committed to differentiation and the cornified layer, where differentiated squames are produced. During this differen- tiation process there are tightly regulated programs of gene expression, one well studied example being the change in expres- sion of keratins from the basal to the suprabasal layers. Keratinocytes produce large amounts of keratin for intermediate filaments, giving the keratinocytes their characteristic strength. There are human inherited disorders that disrupt the correct formation of keratin filaments. Mutations in the basal keratins 5 and 14 leads to the autosomal dominant disease epidermolysis bullosa simplex (Coulombe et al ., 1991, MIM:131760), in which the epidermis blisters upon mild trauma, due to degeneration and rupture of basal keratinocytes. Mutations in the suprabasal kera- tin, keratin 10, cause the disease, epidermolytic hyperkeratosis, which causes a similar degeneration and blistering, but in the suprabasal layers of the epidermis (Rothnagel et al ., 1992, MIM: 600648), Mutations the palmoplantar keratin 9, lead to the same phenotype being restricted to the palms and feet (MIM: 144200, Rothnagel et al ., 1995). Transgenic mouse models in which the human mutant keratin is expressed at the same level as the wildtype keratin, produce phenotypes analogous to the inherited diseases (Fuchs et al ., 1992; Cao et al ., 2001). In almost all cases of keratin mutations, the mutation interferes with the region of the keratin monomers required for proper assembly of intermediate filaments.Mutations in other keratins cause diseases that have more in common with ectodermal dysplasia than epidermolysis. Mutations in the suprabasal keratins 6 and 16 cause a disorder known as pachyonychia congenita (PC1, MIM: 167200), in which there are severe nail defects, as well as palmoplantar hyperkera- tosis, follicular hyperkeratosis and oral leukoplakia (McLean et Fig. 3. The mammalian hedgehog pathway. Smoothened (SMO) can only
Interestingly, previous work showed exencephaly in Fat1 −/− embryos only when Fat4 was also deleted (Saburi et al., 2012). This difference is likely to be due to the different genetic backgrounds of the mouse strains used to breed our Fat1 and Fat4 mutant mice. Indeed, crossing Fat1 +/− ; Fat4 +/− mice onto a number of different mice strains confirmed this hypothesis (supplementary material Fig. S4A). We found that the exencephaly phenotype is primarily dependent on loss of both Fat1 alleles, with enhancement from additional loss of Fat4 alleles occurring in a few genetic backgrounds. In outbred CD-1 mice, for example, deletion of Fat1 alone results in exencephaly in ∼ 20-30% of progeny, with no effects from additional loss of Fat4, whereas the frequency of the phenotype increased from 20% (1/5) to 57% (4/7) upon loss of one allele of Fat4 in a mixed 129/B6 background (supplementary material Fig. S4A). Thus, depending on the genetic strain of the mice, Fat4 and other unknown genetic modifiers play redundant, compensatory roles with regard to the cranial NTD caused by loss of Fat1.
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Angelman syndrome (AS) is a severe neurodevelopmental disorder that occurs in approximately one out of every 12,000 births. Patients with AS exhibit developmental delay, speech impairments, intellectual disability, epilepsy, abnormal electroencephalograms, puppet-like ataxic movements, prognathism, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, hyperactivity, and a high prevalence of autism [1, 2]. Genetic studies revealed that AS is associated with maternal deletions of chromosome 15q11-q13, paternal chromosome 15 uniparental disomy, or rare imprinting defects that affect the transcription of genes within the 15q11-q13 region. Specific loss-of-function mutations in the maternally inherited UBE3A gene which resides within this chromosomal region have been identified in a subset of affected individuals . The UBE3A gene encodes an E3 ubiquitin ligase called UBE3A or E6-associated protein (E6AP). More recently, a mutation in the HERC2 gene has been linked to neurodevelopmental delay and dysfunction in both AS and autism-spectrum disorders among the Old Order Amish [4, 5]. Molecular analysis associated a missense mutation in the HERC2 gene (c.1781C>T, p.Pro594Leu) with the disease phenotype. Although the HERC2 gene also resides in the 15q11-q13 region, it seems that it is not imprinted . HERC2 encodes an ubiquitin ligase that binds to UBE3A and stimulates its ubiquitin ligase activity . Deregulation of the activity of UBE3A is well recognized as contributing to the development of AS [2, 3]. Thus, disruption of HERC2 function by this mutation is associated with a reduction in UBE3A activity resulting in neurodevelopmental delay with Angelman-like features [4, 5].
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PCE has not been tested in the tetradecanoylphorbol ace- tate (TPA)-treated mouse ear model of inflammation. This model evaluates whether pharmaceutical agents or natu- ral products may block the inflammatory response to top- ical TPA [19-21]. Because PCE is being used as an ingredient in cosmeceutical products that are applied to the skin and in nutraceutical products that are ingested, it is worthwhile to test PCE activity in this model. The skin and gastrointestinal mucosa are both subject to inflam- mation, but it is far easier to screen for anti-inflammatory effects on an accessible surface than on an internal epithe- lium. Therefore, the present study tested whether PCE has topical anti-inflammatory activities in the well-character- ized TPA-induced mouse ear model of inflammation, edema, and PMN leukocyte infiltration [22,23]. Total phenolics and ferric reducing antioxidant power (FRAP values) were measured in the ethanolic PCE because both characteristics may reflect the degree of anti-inflammatory activity of the preparation. For example, Chung et. al. reported that edema formation in the TPA model may be regulated by H 2 O 2 generation , as evidenced by anti- inflammatory activity of several antioxidant compounds [25,26].
The gut microbiome is an integral and an important symbiotic system present in the gut, which comprises of bacteria, archaea, fungi and viruses residing in the gastrointestinal tract throughout its length. The gut bacteria itself comprises a major percentage of the total gut microbiome, where its numbers are in trillions. While the stomach and duodenum contain about 10 1 to 10 2 Colony Forming Units (CFU) per mL of bacterial forms, the jejunum and ileum comprise 10 4 to 10 8 , and the colon has 10 10 to 10 12 CFU/mL of bacteria (Cresci & Bawden, 2015). The microbiome acts advantageous for the gut such that it regulates gut epithelial and endocrine cellular structure (Uribe, et al., 1994). Previously, many studies have demonstrated an alteration in gut microbiota to be linked to a variety of conditions including diabetes, arthritis, colitis and cancer and even immune system. Conditions such as Crohn’s disease and obesity have implicated gut bacterial dysbiosis in pathogenesis (Chan, et al., 2015; Mai, et al., 2007). It was not clear if the bacterial dysbiosis is a cause or consequence of the disease until recently when it was shown that alterations in gut microbiome precede polyposis in the Apc Min/+ mouse (Son, et al., 2015). An altered
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CONCLUSION: Lead is a strong teratogen which causes most of its congenital effect at the time of organogenesis during embryonic period. The results of present investigation clearly emphasize that prenatal lead exposure is extremely dangerous and a strong correlation between maternal and umbilical cord blood lead levels indicating prenatal transfer of lead from mother to developing fetus in uterus. Lead suppresses the development of primordial follicles during fetal and neonatal life. Severe pathological changes in primary and secondary follicles with increased number of atretic follicles were also observed.
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There is currently a lack of effective drugs for leg ischemia and no effective drug development pipeline (Gerhard-Herman, Gornik et al. 2016). Pharmacological interventions that have been successful in the acute HLI model have not proved to be effective in large clinical trials (Annex 2013, Dragneva, Korpisalo et al. 2013, Lotfi, Patel et al. 2013, Krishna, Moxon et al. 2015, Mohamed Omer, Krishna et al. 2016). The inability to translate findings from previous pre- clinical studies to patients could be due to the lack of relevant experimental limb ischaemia models and appropriate study design. Current HLI models do not simulate a more typical patient presentation of PAD, such as an ongoing state of ischemia arising from chronic ischaemic insult to the limb, old age and atherosclerosis (Dragneva, Korpisalo et al. 2013, Krishna, Omer et al. 2016, Mohamed Omer, Krishna et al. 2016). In contrast to human PAD, most previous pre-clinical trials are designed to assess potential interventions within model rodents in which ischaemia is not established (Takahashi, Shibata et al. 2015). This prophylactic approach does not represent the clinical situation where treatment usually occurs following the presentation and diagnosis of established chronic ischemia. In addition, many previous studies are not designed to include appropriate measures to limit potential observer bias such as blinding the investigators who are conducting outcome assessments, and lack of allocation randomisation (Mohamed Omer, Krishna et al. 2016).
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As already described, Igf2r plays a balancing, but in essence negative role on growth by removing the excess of IGF-II. Genetic analyses of the effects of transmission of malsegregated, rear- ranged chromosomes, used to study the phenomenon of imprint- ing, revealed that an unnamed growth control gene (potentially antagonizing IGF action) is located somewhere in the proximal third of mouse chromosome 11 (centromere to 11A/B border; Cattanach and Kirk, 1985; Cattanach, 1986; Cattanach et al., 1996; Beechey and Cattanach, 1997). Maternal disomy for the proximal 11 region results in dwarfism, whereas paternal disomy results in overgrowth. The manifestations (in either direction), which are strikingly similar to those observed from lack or overexpression of Igf2, are evident as early as e12.5, and the respective birthweights are 60%N and 140%N. These relative sizes of mice change very little, if at all, postnatally. Except for their sizes, the mice of both sexes are normal and fertile; organ weights are proportional to body weights; and the level of circulating IGF- I is normal. The gene encoding Grb10 (growth factor receptor bound protein 10), a signaling effector inhibiting IGF1R-mediated cell proliferation (Morrione et al., 1997a), has been proposed as a likely candidate for the imprinted gene on proximal 11 (Miyoshi et al., 1998). The hypothesis is that, because the imprinted Grb10 (chromosome 11; 8 cM) is expressed maternally, absence of its negative action on IGF-dependent growth promotion results in overgrowth in the case of paternal disomy of proximal 11. Recip- rocally, overexpression due to maternal disomy leads to dwarfism. Another general growth inhibitory function was revealed when three groups knocked-out independently, and with overall consist- ent results, the gene encoding the p27 Kip1 cyclin-dependent kinase
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Fig 1. Generation of a Tuba8 knockout allele. A) Design of the targeting construct. A 9.1-kb SbfI–NgoAIV genomic fragment was directionally cloned into the SbfI+AgeI-restricted pUC19 vector. The shaded numbered boxes depict exons 2–4. The arrows represent the location and direction of expression of the selectable markers. The neomycin ( neo ) cassette, obtained from PGKneobpA , was inserted at the PspoMI site. The FRT sites (shaded arrow heads) flanked the neomycin positive selection cassette, whilst one LoxP site flanked one side of the neo , and the second was inserted into the BbvCI site in intron 3 (unshaded arrow heads). The diphtheria toxin negative selection cassette, PGK-DTA (kindly provided by P. Soriano, Fred Hutchinson Cancer Research Center, Seattle, WA), was inserted between the SalI and NotI sites of the modified pUC19 backbone. B) Quantitative reverse transcription PCR. Tuba8 mRNA levels in testis were determined from four animals of each Tuba8 genotype, wild type (+/+), heterozygous (+/ − ) and homozygous ( − / − ), and normalised to Hprt levels. Bars indicate mean ± 1 s.d. Statistical significance was reached for all combinations of genotypes using an unpaired t-test (p<0.05). C) Protein analysis using western blotting. Protein lysates from testis samples used four animals of each genotype: wild type (+/+), heterozygous (+/−) and homozygous (−/−), in lanes 1–3 respectively, were probed with the Bioserv Tuba8 mouse monoclonal antibody. A band of approximately 55 kDa was detected in the wild type and heterozygous samples. The blots were subsequently probed for Gapdh expression as a loading control to quantify expression.
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ABSTRACT The X-linked tabby (Ta) syndrome in the mouse is homologous to the hypohidrotic ectodermal dysplasia (HED) in humans. As in humans with HED, Ta mice exhibit hypohidrosis, characteristic defects of hairs and tooth abnormalities. To analyze the effects of Ta mutation on lower incisor development, histology, morphometry and computer-aided 3D reconstructions were combined. We observed that Ta mutation had major consequences for incisor development leading to abnormal tooth size and shape, change in the balance between prospective crown- and root- analog tissues and retarded cytodifferentiations. The decrease in size of Ta incisor was observed at ED13.5 and mainly involved the width of the tooth bud. At ED14.5-15.5, the incisor appeared shorter and narrower in the Ta than in the wild type (WT). Growth alterations affected the diameter to a greater extent than the length of the Ta incisor. From ED14.5, changes in the shape interfered with the medio-lateral asymmetry and alterations in the posterior growth of the cervical loop led to a loss of the labio-lingual asymmetry until ED17.0. Although the enamel organ in Ta incisors was smaller than in the WT, a larger proportion of the dental papilla was covered by preameloblasts-ameloblasts. These changes apparently resulted from reduced development of the lingual part of the enamel organ and might be correlated with a possible heterogeneity in the development of the enamel organ, as demonstrated for upper incisors. Our observations suggest independent development of the labial and lingual parts of the cervical loop. Furthermore, it appeared that the consequences of Ta mutation could not be interpreted only as a delay in tooth development.
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