RESUMEN
Modifications to highly conserved developmental gene regulatory networks are thought to underlie morphological diversification in evolution and contribute to human congenital malformations. Relationships between gene expression and morphology have been extensively investigated in the limb, where most of the evidence for alterations to gene regulation in development consists of pre-transcriptional mechanisms that affect expression levels, such as epigenetic alterations to regulatory sequences and changes to cis-regulatory elements. Here we report evidence that alternative splicing (AS), a post-transcriptional process that modifies and diversifies mRNA transcripts, is dynamic during limb development in two mammalian species. We evaluated AS patterns in mouse (Mus musculus) and opossum (Monodelphis domestica) across the three key limb developmental stages: the ridge, bud, and paddle. Our data show that splicing patterns are dynamic over developmental time and suggest differences between the two mammalian taxa. Additionally, multiple key limb development genes, including Fgf8, are differentially spliced across the three stages in both species, with expression levels of the conserved splice variants, Fgf8a and Fgf8b, changing across developmental time. Our data demonstrates that AS is a critical mediator of mRNA diversity in limb development and provides an additional mechanism for evolutionary tweaking of gene dosage.
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Empalme Alternativo , Extremidades , Factor 8 de Crecimiento de Fibroblastos , Regulación del Desarrollo de la Expresión Génica , Animales , Ratones , Extremidades/embriología , Extremidades/crecimiento & desarrollo , Factor 8 de Crecimiento de Fibroblastos/genética , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Monodelphis/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.
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Región Branquial , Proteínas de Unión a la Región de Fijación a la Matriz , Fenotipo , Factores de Transcripción , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Animales , Humanos , Ratones , Factores de Transcripción/genética , Región Branquial/anomalías , Región Branquial/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Femenino , Masculino , Ratones Noqueados , Síndrome , Mandíbula/anomalías , Mandíbula/patologíaRESUMEN
Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic. Five individuals (5/32, 16%) were documented to have BMD Z-scores by DXA scans of -2.0 SD or lower and 7 more (7/32, 22%) had Z-scores between -1 and - 2 SD at the lumbar spine or the total hip. Alkaline phosphatase levels were found to be elevated in 19 individuals (19/30, 63%) and determined to correspond to bone-specific alkaline phosphatase elevations when measured (11/11, 100%). C-telopeptide levels were found to be elevated when adjusted by age and gender in 6 individuals (6/14, 43%). Additionally, the two individuals who underwent bone cross-sectional geometry evaluation by peripheral quantitative computed tomography were documented to have low cortical bone density for age and sex despite concurrent DXA scans that did not have this level of decreased density. While we could not identify particular biochemical abnormalities that predicted low BMD, the frequent elevations in markers of bone formation and resorption further confirmed the increased bone turnover in SAS. Based on our results and other recently published studies, we propose surveillance guidelines for the skeletal phenotype of SAS.
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Enfermedades Óseas Metabólicas , Proteínas de Unión a la Región de Fijación a la Matriz , Femenino , Humanos , Masculino , Densidad Ósea/genética , Fosfatasa Alcalina , Estudios Prospectivos , Huesos/diagnóstico por imagen , Absorciometría de Fotón/métodos , Síndrome , Factores de Transcripción/genética , Proteínas de Unión a la Región de Fijación a la Matriz/genéticaRESUMEN
Introduction: The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Formation of ectodermal-endodermal interfaces is a key mediator of this process, and although it is essential, mechanisms regulating the establishment of these interfaces vary between pouches and between taxa. Methods: Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes in the mouse model system. Results: We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Discussion: Based on Fgf8-mediated changes in tissue relationships between pp1 and pc1, we hypothesize that extension of pp1 requires physical interaction with pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.
RESUMEN
The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Out-pocketing of the pharyngeal endoderm between the arches is a key mediator of this process, and although it is essential, mechanisms regulating out-pocketing vary between pouches and between taxa. Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes. We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that extension of pp1 requires physical interaction with pc1, and that multiple aspects of pc1 morphogenesis require Fgf8 . In particular, Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.
RESUMEN
AIM: This study aimed to investigate the levels of nurses' organizational citizenship behaviour and the associations between job burnout and ethical climate with organizational citizenship behaviour. BACKGROUND: Organizational citizenship behaviour improves adverse outcomes led by nursing shortage. However, the associations between three dimensions of job burnout and organizational citizenship behaviour are inconsistent, and little is known about whether ethical climate is related to organizational citizenship behaviour in nurses. METHODS: In this cross-sectional study, 1157 nurses were selected using convenience sampling from April to October 2019. Self-report surveys assessed nurses' organizational citizenship behaviour, emotional exhaustion, depersonalization, personal accomplishment and perceptions of ethical climate. RESULTS: Mean organizational citizenship behaviour was high among nurses. The regression model showed that job burnout and ethical climate explained an additional 38.6% of the variance in organizational citizenship behaviour over and above sociodemographic factors, with 44.9% of the total variance. CONCLUSION: Nurses' organizational citizenship behaviour was at a relatively high level. Depersonalization was negatively associated with organizational citizenship behaviour while personal accomplishment and ethical climate were positively related to organizational citizenship behaviour. Therefore, nurse leaders are encouraged to take measures to help nurses reduce job burnout and create a favourable ethical climate for increasing nurses' organizational citizenship behaviour.
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Agotamiento Profesional , Enfermeras y Enfermeros , Personal de Enfermería en Hospital , Humanos , Estudios Transversales , Ciudadanía , Satisfacción en el Trabajo , Agotamiento Profesional/psicología , Enfermeras y Enfermeros/psicología , Encuestas y Cuestionarios , Cultura Organizacional , Personal de Enfermería en Hospital/psicologíaRESUMEN
BACKGROUND: Asymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. RESULTS: Developmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-specimen variation. CONCLUSIONS: We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.
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Región Branquial , Corazón , Animales , Factor 8 de Crecimiento de Fibroblastos/genética , Humanos , Anomalías Maxilomandibulares , Maxilar , Ratones , Anomalías de la BocaRESUMEN
AIMS: To compare levels of nurse burnout across eastern and western cultures, as well as examine the influence of burnout on patient safety cross-culturally. DESIGN: Comparative cross-sectional study. METHODS: Survey data were collected from nurses between August and October 2017 in Australia (n = 730) and between April and October 2019 in China (n = 1107). Variables included burnout (emotional exhaustion, depersonalization, personal accomplishment), nurse leadership and support, staffing and resource adequacy, and perceived patient safety. Data were analysed separately for each jurisdiction using bootstrapped hierarchical regressions, which tested the relationships between burnout indicators and patient safety, controlling for support resources. RESULTS: Emotional exhaustion and depersonalization scores were significantly higher in the Australian sample compared with the Chinese sample. Australian participants reported significantly lower patient safety grades than Chinese participants and were less likely to agree that support resources were present in their current job. Separate regressions indicated that patient safety was significantly associated with staffing and resource adequacy, nurse leadership and support, and depersonalization among Australian participants (30% of variance explained in the final regression model), while staffing and resource adequacy, nurse leadership and support, personal accomplishment and emotional exhaustion predicted patient safety for Chinese participants (22% of variance explained in the final model). CONCLUSION: Australian nurses are at greater risk of burnout than Chinese nurses. Burnout dimensions are differentially associated with patient safety across cultures. Culturally relevant interventions may be more optimal than universal approaches for improving burnout and patient safety in nursing. IMPACT: This study increased understanding of cross-cultural differences in nurse burnout and the relationship with patient safety. Australian nurses were at greater risk of burnout than Chinese nurses. Emotional exhaustion, depersonalization and personal accomplishment influenced patient safety distinctively across the countries. These findings inform interventions designed to reduce nurse burnout and improve patient safety internationally.
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Agotamiento Profesional , Comparación Transcultural , Australia , Agotamiento Profesional/psicología , Estudios Transversales , Humanos , Satisfacción en el Trabajo , Encuestas y CuestionariosRESUMEN
EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3. Exon skipping in Mdm2 was also increased in O9-1 mouse neural crest cells after siRNA knock-down of Eftud2 and in MFDM patient cells. Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death. Finally, overactivation of the P53 pathway in Eftud2 knockdown cells was attenuated by overexpression of non-spliced Mdm2, and craniofacial development was improved when Eftud2-mutant embryos were treated with Pifithrin-α, an inhibitor of P53. Thus, our work indicates that the P53-pathway can be targeted to prevent craniofacial abnormalities and shows a previously unknown role for alternative splicing of Mdm2 in the etiology of MFDM.
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Ribonucleoproteína Nuclear Pequeña U5 , Proteína p53 Supresora de Tumor , Animales , Homocigoto , Humanos , Ratones , Mutación , Factores de Elongación de Péptidos/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ribonucleoproteína Nuclear Pequeña U5/genética , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
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Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Proteínas de Unión a la Región de Fijación a la Matriz/deficiencia , Factores de Transcripción/deficiencia , Adulto , Niño , Preescolar , Cromosomas Humanos Par 2/ultraestructura , Colágeno Tipo III/deficiencia , Colágeno Tipo III/genética , Colágeno Tipo V/deficiencia , Colágeno Tipo V/genética , Enanismo/genética , Cara/anomalías , Femenino , Estudios de Asociación Genética , Edad Gestacional , Humanos , Hipertensión Pulmonar/genética , Lactante , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Microcefalia/genética , Fenotipo , Delgadez/genética , Factores de Transcripción/genéticaRESUMEN
Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children.
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Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Interleucina-13/biosíntesis , Hipersensibilidad al Cacahuete/inmunología , Células Th2/inmunología , Adolescente , Aminoglutetimida/farmacología , Línea Celular , Niño , Preescolar , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/antagonistas & inhibidores , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Femenino , Técnicas de Inactivación de Genes , Humanos , Activación de Linfocitos , Masculino , Hipersensibilidad al Cacahuete/sangre , ARN Mensajero/genética , Transfección , Adulto JovenRESUMEN
BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
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Epilepsia , Enfermedades Genéticas Congénitas , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Malformaciones del Sistema Nervioso , Trastornos del Sueño-Vigilia , Factores de Transcripción/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/etiología , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/fisiopatología , Humanos , Lactante , Masculino , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/etiología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Estudios Retrospectivos , Fases del Sueño/fisiología , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/genética , Trastornos del Sueño-Vigilia/fisiopatología , Síndrome , Adulto JovenRESUMEN
Special AT-rich sequence binding protein 2 (Satb2) is a matrix attachment region (MAR) binding protein. Satb2 impacts skeletal development by regulating gene transcription required for osteogenic differentiation. Although its role as a high-order transcription factor is well supported, other roles for Satb2 in skeletal development remain unclear. In particular, the impact of dosage sensitivity (heterozygous mutations) and variance on phenotypic severity is still not well understood. To further investigate molecular and cellular mechanisms of Satb2-mediated skeletal defects, we used the CRISPR/Cas9 system to generate Satb2 mutations in MC3T3-E1 cells. Our data suggest that, in addition to its role in differentiation, Satb2 regulates progenitor proliferation. We also find that mutations in Satb2 cause chromatin defects including nuclear blebbing and donut-shaped nuclei. These defects may contribute to a slight increase in apoptosis in mutant cells, but apoptosis is insufficient to explain the proliferation defects. Satb2 expression exhibits population-level variation and is most highly expressed from late G1 to late G2. Based on these data, we hypothesize that Satb2 may regulate proliferation through two separate mechanisms. First, Satb2 may regulate the expression of genes necessary for cell cycle progression in pre-osteoblasts. Second, similar to other MAR-binding proteins, Satb2 may participate in DNA replication. We also hypothesize that variation in the severity or penetrance of Satb2-mediated proliferation defects is due to stochastic variation in Satb2 binding to DNA, which may be buffered in some genetic backgrounds. Further elucidation of the role of Satb2 in proliferation has potential impacts on our understanding of both skeletal defects and cancer.
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Núcleo Celular/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Osteoblastos/citología , Osteoblastos/metabolismo , Factores de Transcripción/genética , Animales , Sistemas CRISPR-Cas/genética , Ciclo Celular/genética , Diferenciación Celular/genética , Línea Celular , Forma del Núcleo Celular , Proliferación Celular , Regulación de la Expresión Génica , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Ratones , Modelos Biológicos , Mutación/genética , Osteogénesis/genética , Factores de Transcripción/metabolismoRESUMEN
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
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Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mutación , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Animales , Niño , Preescolar , Codón de Terminación , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Estudios de Asociación Genética , Humanos , Masculino , Mutación Missense , Polimorfismo de Nucleótido SimpleRESUMEN
Canalization, or robustness to genetic or environmental perturbations, is fundamental to complex organisms. While there is strong evidence for canalization as an evolved property that varies among genotypes, the developmental and genetic mechanisms that produce this phenomenon are very poorly understood. For evolutionary biology, understanding how canalization arises is important because, by modulating the phenotypic variation that arises in response to genetic differences, canalization is a determinant of evolvability. For genetics of disease in humans and for economically important traits in agriculture, this subject is important because canalization is a potentially significant cause of missing heritability that confounds genomic prediction of phenotypes. We review the major lines of thought on the developmental-genetic basis for canalization. These fall into two groups. One proposes specific evolved molecular mechanisms while the other deals with robustness or canalization as a more general feature of development. These explanations for canalization are not mutually exclusive and they overlap in several ways. General explanations for canalization are more likely to involve emergent features of development than specific molecular mechanisms. Disentangling these explanations is also complicated by differences in perspectives between genetics and developmental biology. Understanding canalization at a mechanistic level will require conceptual and methodological approaches that integrate quantitative genetics and developmental biology.
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Evolución Biológica , Epigénesis Genética , Epistasis Genética , Estudios de Asociación Genética , Genotipo , Fenotipo , Adaptación Fisiológica/genética , Animales , Biología Evolutiva/métodos , Redes Reguladoras de Genes , Interacción Gen-Ambiente , Técnicas Genéticas , Variación Genética , Genética , Humanos , Plantas/genética , Carácter Cuantitativo Heredable , Selección GenéticaRESUMEN
The skull is a vertebrate novelty. Morphological adaptations of the skull are associated with major evolutionary transitions, including the shift to a predatory lifestyle and the ability to masticate while breathing. These adaptations include the chondrocranium, dermatocranium, articulated jaws, primary and secondary palates, internal choanae, the middle ear, and temporomandibular joint. The incredible adaptive diversity of the vertebrate skull indicates an underlying bauplan that promotes evolvability. Comparative studies in craniofacial development suggest that the craniofacial bauplan includes three secondary organizers, two that are bilaterally placed at the Hinge of the developing jaw, and one situated in the midline of the developing face (the FEZ). These organizers regulate tissue interactions between the cranial neural crest, the neuroepithelium, and facial and pharyngeal epithelia that regulate the development and evolvability of the craniofacial skeleton.
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Evolución Biológica , Huesos Faciales/embriología , Cresta Neural/embriología , Cráneo/embriología , Animales , Tipificación del Cuerpo/genética , Huesos Faciales/anatomía & histología , Huesos Faciales/metabolismo , Peces/anatomía & histología , Peces/embriología , Peces/genética , Regulación del Desarrollo de la Expresión Génica , Cresta Neural/anatomía & histología , Cresta Neural/metabolismo , Cráneo/anatomía & histología , Cráneo/metabolismoRESUMEN
Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.
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Desarrollo Óseo/genética , Disostosis Craneofacial/genética , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Animales , Disostosis Craneofacial/metabolismo , Humanos , Empalme del ARN , Ribosomas/genética , Cráneo/embriología , Cráneo/metabolismoRESUMEN
OBJECTIVE: To characterize the radiographic dental phenotype of individuals with SATB2-associated syndrome (SAS). MATERIALS AND METHODS: Participants were evaluated by a multidisciplinary team during a concurrent clinic conducted during the 1st international SAS family meeting held in 2017 at a single institution. Whenever possible, panoramic and/or periapical radiographs were obtained in clinic or previously obtained and provided by the caregiver. RESULTS: Of the 37 individuals evaluated, 18 (12 males, median age 8.5 years) underwent radiographic examination. Dental radiographs revealed anomalies in all individuals starting at 2 years of age. The most consistent finding was delayed development of the mandibular second bicuspids (83%) with other common radiographic findings including delayed development of the roots of the permanent teeth (78%), severely rotated (56%) or malformed teeth (44%), and taurodontism (44%). CONCLUSIONS: Dental anomalies are fully penetrant and can be documented radiographically in all individuals with SAS. CLINICAL RELEVANCE: Dental radiographic findings of delayed second premolar development and delayed development of permanent root formation, especially concurrent with findings of taurodontism and malformed teeth, support a clinical suspicion for SAS and should help differentiate SAS from other neurodevelopmental syndromes.
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Cavidad Pulpar/anomalías , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/genética , Adolescente , Niño , Preescolar , Cavidad Pulpar/diagnóstico por imagen , Femenino , Humanos , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz , Fenotipo , Radiografía Dental , Radiografía Panorámica , Síndrome , Factores de Transcripción , Adulto JovenRESUMEN
Objective: To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods: Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results: In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion: Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS.