RESUMO
BACKGROUND: Fabry disease (FD) is an X-linked inherited disease where renal complications are associated with a poor prognosis. However, little is known about the prevalence of Fabry nephropathy (FN) in patients with chronic kidney disease (CKD). We extracted FN data from the Japan Renal Biopsy Registry, analyzed the prevalence of FN, and examined the correlation between clinical characteristics and renal involvement according to sex differences and hemi- and heterozygosity in patients with FD. METHODS: A total of 38,351 participants who underwent renal biopsy were retrospectively enrolled, and FN was determined. The clinical characteristics of FD patients were examined based on sex differences. RESULTS: Twenty-nine patients (0.076%) (19 males and 10 females, mean age: 43.7 ± 15.5 years old) were diagnosed with FN. Median estimated urinary protein (UP) and mean eGFR levels were 0.9 [interquartile range (IQR) [0.7-1.6] g/gCr and 67.1 ± 36.8 mL/min/1.73 m2, respectively. Mean systolic blood pressure (SBP) was 126.4 ± 17.1 mmHg and diastolic blood pressure was 76.1 ± 12.6 mmHg. An inverse correlation between eGFR and logarithm UP levels was observed (r2 = 0.23, p = 0.02), SBP was positively associated with logarithm UP (r2 = 0.34, p = 0.004) overall and inversely associated with eGFR (r2 = 0.25, p = 0.007) regardless of sex, and SBP was an independent determinant of proteinuria (p = 0.004) and eGFR (p = 0.007). CONCLUSIONS: The prevalence of biopsy-proven FN was 0.076%. Since SBP is associated with eGFR regardless of zygosity, strict SBP control might be necessary to prevent progression to end-stage kidney disease in both male and female patients with FN.
Assuntos
Doença de Fabry , Insuficiência Renal Crônica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biópsia , Estudos Transversais , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Taxa de Filtração Glomerular , Japão/epidemiologia , Sistema de Registros , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder caused by a deficiency in alfa-galactosidase A (α-Gal A) activity due to mutations in the GLA gene, has a prevalence of 0-1.69% in patients undergoing haemodialysis; however, its prevalence in patients with chronic kidney disease (CKD) Stages 1-5 is unknown. METHODS: Serum α-Gal A activity analysis and direct sequencing of GLA were used to screen for FD in 2122 male patients with CKD, including 1703 patients with CKD Stage 5D and 419 with CKD Stages 1-5. The correlation between serum α-Gal A activity and confounding factors in patients with CKD Stages 1-5 was evaluated. RESULTS: FD prevalence rates in patients with CKD Stage 5D and CKD Stages 1-5 were 0.06% (1/1703) and 0.48% (2/419), respectively. A patient with CKD Stage 5D exhibited a novel GLA mutation, p.Met208Arg, whereas two patients with CKD Stages 1-5 had c.370delG and p.Met296Ile. p. Met208Arg caused moderate structural changes in the molecular surface region near the substituted amino acid residue but did not affect the catalytic residues Asp170 and Asp231 in α-Gal A. Serum α-Gal A activity in patients with CKD Stages 1-5 was inversely correlated with age (P < 0.0001) but directly correlated with estimated glomerular filtration rate (P < 0.0001). CONCLUSIONS: FD prevalence was much higher in male patients with CKD Stages 1-5 than in those with CKD Stage 5D. FD screening in patients with CKD Stages 1-5 may improve patient survival, decreasing the number of patients with CKD Stage 5D.
Assuntos
Doença de Fabry , Insuficiência Renal Crônica , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Mutação , Diálise Renal , Insuficiência Renal Crônica/epidemiologia , alfa-Galactosidase/genéticaRESUMO
The telencephalon is one of the most-elaborated tissues. A broad variety of cell types is produced by spatiotemporally regulated mechanisms and is involved, in different combinations, in subregional formation. The dorsal half of the telencephalon, the pallium or cerebral cortex, is subdivided along the dorsal-ventral (D-V) axis into the medial, dorsal, lateral, and ventral pallium (MP, DP, LP and VP, respectively). An in vitro differentiation system has been achieved using mouse embryonic stem cells, and major telencephalic neurons can be obtained in this way; however, in using the in vitro differentiation system, many telencephalic neuron subtypes remain undifferentiated, although some of them are related to neuronal diseases. In the current study, we found that inhibiting the TGFbeta signal was efficient for neural induction. A continuous arrangement of Emx1+/Pax6-, Emx1+/Pax6+, and Emx1-/Pax6+ cells was achieved in Foxg1+ neuroepithelia, corresponding approximately to cortical progenitors derived from MP, DP/LP, and VP, respectively. A small portion of Dbx1+ cells resided in the VP fraction. These findings suggested that the D-V axis of the pallium was recapitulated in the in vitro-derived pallium.
Assuntos
Córtex Cerebral/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Neurônios/metabolismo , Telencéfalo/metabolismo , Animais , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/farmacocinética , Camundongos , Fator de Transcrição PAX6/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Pou3f2/Brn2 is a transcription factor that helps to determine the cellular identity of neocortical or hypothalamic neurons. Mammalian Pou3f2 contains three homopolymeric amino acids that are not present in amphibian Pou3f2. These amino acids contribute to monoamine function, which may play specific roles in mammalian development and behavior. Previous work has indicated that Pou3f2â¿ mice, which lack the homopolymeric amino acids, exhibited declined maternal activity and impaired object and spatial recognition. The current study, analyzed weight gain, brain development, home cage activity, social interaction, and response to novel objects in Pou3f2â¿ mice to determine which aspects of behavior were affected by monoamine dysregulation. Compared to their wild type counterparts, Pou3f2â¿ mice showed decreased social interaction and reduced home cage activity during their active phase. However, they showed normal weight gain, brain development, and responses to novelty. These results indicate that monoamine dysregulation in Pou3f2â¿ mice may specifically affect basal activity and social development, without altering non-social motivation.
Assuntos
Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fatores do Domínio POU/fisiologia , Comportamento Social , Animais , Monoaminas Biogênicas/fisiologia , Encéfalo/crescimento & desenvolvimento , Comportamento Exploratório/fisiologia , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neocórtex/fisiologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Fatores do Domínio POU/química , Fatores do Domínio POU/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Aumento de PesoRESUMO
The piriform cortex (paleocortex) is the olfactory cortex or the primary cortex for the sense of smell. It receives the olfactory input from the mitral and tufted cells of the olfactory bulb and is involved in the processing of information pertaining to odors. The piriform cortex and the adjoining neocortex have different cytoarchitectures; while the former has a three-layered structure, the latter has a six-layered structure. The regulatory mechanisms underlying the building of the six-layered neocortex are well established; in contrast, less is known about of the regulatory mechanisms responsible for structure formation of the piriform cortex. The differences as well as similarities in the regulatory mechanisms between the neocortex and the piriform cortex remain unclear. Here, the expression of neocortical layer-specific genes in the piriform cortex was examined. Two sublayers were found to be distinguished in layer II of the piriform cortex using Ctip2/Bcl11b and Brn1/Pou3f3. The sequential expression pattern of Ctip2 and Brn1 in the piriform cortex was similar to that detected in the neocortex, although the laminar arrangement in the piriform cortex exhibited an outside-in arrangement, unlike that observed in the neocortex.
Assuntos
Neocórtex/anatomia & histologia , Córtex Piriforme/anatomia & histologia , Animais , Camundongos , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fatores do Domínio POU/metabolismo , Córtex Piriforme/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Tempo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Mammalian adult females develop specialized body parts, namely mammary glands and uterus, and exhibit specialized maternal behavior, lactation/nursing and care for their offspring. As the brain plays an essential role in regulating related physiological functions in the body, the morphology or function of the mammalian brain has been modified to manage newly equipped structures and functions. However, this evolutionary process is largely unknown. Pou3f2/Brn2 is an evolutionarily remarkable gene as it contains mammal-specific base sequences encoding three stretches of homopolymeric amino acids (polyAAs): poly-glycine (polyG), poly-glutamine (polyQ), and poly-proline (polyP). Previously, we demonstrated that POU3F2 acquisition of mammal-specific polyAAs contributed to the establishment of behaviors characteristic of mammals. Here, we demonstrated that Pou3f2â¿ mice displayed basic features required for maternal care. However, Pou3f2â¿ mice exhibited deficits in the reproductive performance and maternal behavior, which were not fully improved by multiparas. Therefore, we extensively investigated pup retrieval behavior and discovered that the retrieval and the exploratory behaviors were impaired in Pou3f2â¿ female mice, but not in males. Altogether, our data suggest that POU3F2 acquisition of mammal-specific polyAAs contributes to the continuous awareness and curiosity needed for maternal interaction.
Assuntos
Comportamento Exploratório , Comportamento Materno , Animais , Encéfalo/metabolismo , Comportamento Exploratório/fisiologia , Feminino , Humanos , Lactação , Masculino , Mamíferos , Comportamento Materno/fisiologia , CamundongosRESUMO
Proper brain development requires precisely controlled phases of stem cell proliferation, lineage specification, differentiation, and migration. Lineage specification depends partly on concentration gradients of chemical cues called morphogens. However, the rostral brain (telencephalon) expands prominently during embryonic development, dynamically altering local morphogen concentrations, and telencephalic subregional properties develop with a time lag. Here, we investigated how progenitor specification occurs under these spatiotemporally changing conditions using a three-dimensional in vitro differentiation model. We verified the critical contributions of three signaling factors for the lineage specification of subregional tissues in the telencephalon, ventralizing sonic hedgehog (Shh) and dorsalizing bone morphogenetic proteins (BMPs) and WNT proteins (WNTs). We observed that a short-lasting signal is sufficient to induce subregional progenitors and that the timing of signal exposure for efficient induction is specific to each lineage. Furthermore, early and late progenitors possess different Shh signal response capacities. This study reveals a novel developmental mechanism for telencephalon patterning that relies on the interplay of dose- and time-dependent signaling, including a time lag for specification and a temporal shift in cellular Shh sensitivity. This delayed fate choice through two-phase specification allows tissues with marked size expansion, such as the telencephalon, to compensate for the changing dynamics of morphogen signals.
RESUMO
Intermediate progenitors of both excitatory and inhibitory neurons, which can replenish neurons in the adult brain, were recently identified. However, the generation of intermediate progenitors of GABAergic inhibitory neurons (IPGNs) has not been studied in detail. Here, we characterized the spatiotemporal distribution of IPGNs in mouse cerebral cortex. IPGNs generated neurons during both embryonic and postnatal stages, but the embryonic IPGNs were more proliferative. Our lineage tracing analyses showed that the embryonically proliferating IPGNs tended to localize to the superficial layers rather than the deep cortical layers at 3 weeks after birth. We also found that embryonic IPGNs derived from the medial and caudal ganglionic eminence (CGE) but more than half of the embryonic IPGNs were derived from the CGE and broadly distributed in the cerebral cortex. Taken together, our data indicate that the broadly located IPGNs during embryonic and postnatal stages exhibit a different proliferative property and layer distribution.
RESUMO
L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (ß = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.
Assuntos
Carnitina/sangue , Carnitina/farmacocinética , Suplementos Nutricionais , Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Carnitina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Coração/fisiopatologia , Insuficiência Cardíaca/complicações , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-CegoRESUMO
Recent studies using human pluripotent stem cells (hPSCs) have developed protocols to induce kidney-lineage cells and reconstruct kidney organoids. However, the separate generation of metanephric nephron progenitors (NPs), mesonephric NPs, and ureteric bud (UB) cells, which constitute embryonic kidneys, in in vitro differentiation culture systems has not been fully investigated. Here, we create a culture system in which these mesoderm-like cell types and paraxial and lateral plate mesoderm-like cells are separately generated from hPSCs. We recapitulate nephrogenic niches from separately induced metanephric NP-like and UB-like cells, which are subsequently differentiated into glomeruli, renal tubules, and collecting ducts in vitro and further vascularized in vivo. Our selective differentiation protocols should contribute to understanding the mechanisms underlying human kidney development and disease and also supply cell sources for regenerative therapies.
Assuntos
Técnicas de Cultura de Células/métodos , Linhagem da Célula/fisiologia , Células-Tronco Pluripotentes/citologia , Diferenciação Celular/fisiologia , Células Cultivadas , Células Epiteliais , Humanos , Rim/citologia , Mesoderma , Néfrons , Organogênese/fisiologia , Organoides/citologia , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/fisiologiaRESUMO
While pancreatic islet transplantation achieves insulin independence in type 1 diabetes (T1D) patients, its widespread application is limited by donor tissue scarcity. Pancreatic progenitor cells (PPCs) give rise to all cell types in the pancreas during development. PPCs derived from human pluripotent stem cells have been shown to differentiate into functional ß cells both in vitro and in vivo, and to reverse hyperglycemia, at least in mice. Therefore, PPCs have great potential to serve as an alternative cell source for cell therapy, and the identification of compounds that facilitate PPC proliferation could provide stable and large-scale pancreatic cell preparation systems in clinical settings. Here, we developed and performed cell-based screens to identify small molecules that induce the proliferation of hiPSC-derived PDX1-expressing PPCs. The screening identified AT7867, which promoted PPC proliferation approximately five-fold within six days through the maintenance of a high Ki67+ cell ratio. The induced proliferation by AT7867 does not result in DNA damage, as revealed by pHH2AX staining, and is observed specifically in PPCs but not other cell types. The established platform utilizing small molecules for PPC proliferation may contribute to the development of cell therapy for T1D using a regenerative medicine approach.
Assuntos
Proteínas de Homeodomínio/metabolismo , Pâncreas/citologia , Piperidinas/farmacologia , Células-Tronco Pluripotentes/citologia , Pirazóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Transativadores/metabolismo , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/metabolismo , Piperidinas/química , Células-Tronco Pluripotentes/metabolismo , Pirazóis/química , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/análiseRESUMO
Brain-2 (Brn-2), a Class III POU transcription factor, plays an important role in the development of the neocortex and the establishment of neural cell lineage. Here we performed a yeast two-hybrid screening to identify the Brn-2 binding proteins. We obtained Jun-activation-domain-binding protein 1 (Jab1) as a new Brn-2 binding protein. Direct interaction between Brn-2 and Jab1 was confirmed by using a surface plasmon resonance biosensor. Considering the involvement of Jab1 in the onset of the neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, the interaction between Brn-2 and Jab1 may provide some insights into the understanding of neuronal development and neurodegenerative diseases.
Assuntos
Proteínas de Ligação a DNA/química , Proteínas do Tecido Nervoso/química , Doenças Neurodegenerativas/fisiopatologia , Peptídeo Hidrolases/química , Fatores de Transcrição/química , Animais , Complexo do Signalossomo COP9 , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Escherichia coli/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Proteínas do Tecido Nervoso/genética , Fatores do Domínio POU , Peptídeo Hidrolases/genética , Ligação Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Ressonância de Plasmônio de Superfície , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Carnitine deficiency may contribute to cardiovascular disease (CVD) in patients with hemodialysis (HD). Dyslipidemia plays a role in CVD and its prevalence is also high in HD patients. We examined here the effects of switching from oral administration (PO) to intravenous (IV) injection of l-carnitine on lipid metabolism in patients with HD. METHODS: Nine HD patients who had received l-carnitine orally (900 mg/day) for 1 year were enrolled in this study. We examined whether lipid parameters were improved by switching to IV injection therapy of 1000 mg l-carnitine. RESULTS: IV injection of l-carnitine for 1 week significantly increased total, free and acyl carnitine levels both before and after HD. Switching to IV injection therapy for 1 and 4 weeks decreased serum free fatty acid (FFA) (322 ± 104 versus 261 ± 124 µmol/L) and increased high-density lipoprotein-cholesterol levels (1.46 ± 0.49 versus 1.63 ± 0.62 mmol/L), respectively. Change in FFA values from the baseline (ΔFFA) was positively correlated with the Δacyl/free carnitine ratio (r (2) = 0.553, P = 0.022). CONCLUSION: This study demonstrated that switching to IV l-carnitine therapy from oral supplementation improved lipid profiles, thus supporting the clinical utility of IV administration of l-carnitine for the treatment of patients on HD.
RESUMO
Various mutations have occurred during evolution among orthologs, genes in different species that diverged from a common ancestral gene by speciation. Here, we report the remarkable deterioration of a characteristic mammalian maternal behavior, pup retrieval, in nonmammalized mice, in which the transcription factor Pou3f2 was replaced with the Xenopus ortholog lacking all of the homopolymeric amino acid repeats of mammalian POU3F2. Most of the pups born to the nonmammalized mice died within days after birth, depending on the dam genotype alone. Quantitative immunohistochemical analysis revealed decreases in the rate-limiting enzymes of dopamine and serotonin synthesis in various brain structures. Similar results were obtained in knock-in mice in which all of the homopolymeric amino acid repeats of mammalian POU3F2 were removed. Pup retrieval behavior in mammals is thus strongly related to monoamine neurotransmitter levels via the acquisition of homopolymeric amino acid repeats during mammalian evolution.
Assuntos
Encéfalo/metabolismo , Mamíferos/genética , Comportamento Materno/fisiologia , Proteínas do Tecido Nervoso/genética , Fatores do Domínio POU/genética , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Dopamina/biossíntese , Feminino , Técnicas de Introdução de Genes , Camundongos Mutantes , Proteínas do Tecido Nervoso/metabolismo , Fatores do Domínio POU/metabolismo , Sequências Repetitivas de Aminoácidos , Serotonina/biossíntese , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas de Xenopus/genéticaRESUMO
We investigated the evolutionary conservation of polyglutamine binding protein-1 (PQBP-1) among Vertebrata. PQBP-1s were highly conserved and shared the same domain features including a WW domain, a polar amino acid rich domain (PRD), a nuclear localization signal (NLS), and a C-terminal domain (CTD) among Eutheria, but not always among Vertebrata. PQBP-1s of Vertebrata contained a variable region in the middle portion corresponding to the position of PRD. The full form of PRD including both 7aa and DR/ER repeats was specific to Eutheria. PRD of non-eutherian Amniota was minimal. Amphibia had no PRD. The DR/ER repeat was solo in fishes. Agnatha PRD was also rich in polar amino acids, but contained no repetitive sequence. We investigated 3 polyQ-containing proteins known to interact with PQBP-1: BRN-2, Huntingtin, and ATAXIN-1, and showed a diverse nature of protein-protein interaction in Vertebrata. There appears to be no interaction between PQBP-1 and BRN-2, Huntingtin, or ATAXIN-1 in Amphibia, while the interaction between PQBP-1 and BRN-2 is expected to be conserved among Mammalia, and the interaction between PQBP-1 and Huntingtin or ATAXIN-1 depends on the lineage in Eutheria.
Assuntos
Proteínas de Transporte/química , Proteínas Nucleares/química , Peptídeos/metabolismo , Vertebrados , Sequência de Aminoácidos , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Homologia de Sequência de AminoácidosRESUMO
In the mammalian cortex, the dorsal telencephalon exhibits a characteristic stratified structure. We previously reported that three-dimensional (3D) culture of mouse ES cells (mESCs) can efficiently generate cortical neuroepithelium (NE) and layer-specific cortical neurons. However, the cortical NE generated in this mESC culture was structurally unstable and broke into small neural rosettes by culture day 7, suggesting that some factors for reinforcing the structural integrity were missing. Here we report substantial supporting effects of the extracellular matrix (ECM) protein laminin on the continuous formation of properly polarized cortical NE in floating aggregate culture of mESCs. The addition of purified laminin and entactin (a laminin-associated protein), even at low concentrations, stabilized the formation of continuous cortical NE as well as the maintenance of basement membrane and prevented rosette formation. Treatment with the neutralizing ß1-integrin antibody impaired the continuous NE formation. The stabilized cortical NE exhibited typical interkinetic nuclear migration of cortical progenitors, as seen in the embryonic cortex. The laminin-treated cortical NE maintained a continuous structure even on culture days 12 and 15, and contained ventricular, basal-progenitor, cortical-plate and Cajal-Retzius cell layers. The cortical NE in this culture was flanked by cortical hem-like tissue. Furthermore, when Shh was added, ventral telencephalic structures such as lateral ganglionic eminence-like tissue formed in the region adjacent to the cortical NE. Thus, our results indicate that laminin-entactin ECM promotes the formation of structurally stable telencephalic tissues in 3D ESC culture, and supports the morphogenetic recapitulation of cortical development.
Assuntos
Córtex Cerebral/citologia , Células-Tronco Embrionárias/citologia , Matriz Extracelular/metabolismo , Laminina/metabolismo , Neurônios/citologia , Animais , Membrana Basal/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Células-Tronco Embrionárias/metabolismo , Camundongos , Neurônios/metabolismoRESUMO
Sequence comparison of Hoxd-13 among vertebrates revealed the presence of taxon-specific polyalanine tracts in amniotes. To investigate their function at the organismal level, we replaced the wild-type Hoxd-13 gene with one lacking the 15-residue polyalanine tract by using homologous recombination. Sesamoid bone formation in knock-in mice was different from that in the wild type; this was observed not only in the homozygotes but also in the heterozygotes. The present study provides the first direct evidence that taxon-specific homopolymeric amino acid repeats are involved in phenotypic diversification at the organismal level.