Le développement cranio-facial est un processus complexe qui implique interactions tissulaires et différenciations cellulaires. La façon dont ces processus sont coordonnés lors de l'embryogenèse reste évasive. Perturber ce développement coordonné provoque un large éventail de malformations. Afin de trouver de nouveaux gènes impliqués dans le développement de la tête, un criblage phénotypique a été réalisé par mutagenèse. L'une des lignées de souris obtenues montre des malformations au niveau des arches pharyngées (AP), qui sont les précurseurs de la tête. Ces mutants meurent à mi gestation, due à des problèmes vasculaires. La mutation ponctuelle générée a été localisé dans le gène Mortalin. Mon travail de thèse vise à comprendre comment Mortalin contrôle le développement embryonnaire. Mortalin est exprimée de manière ubiquitaire, puis son expression augmente au niveau des AP, dans les tissus musculaires et nerveux. Pour déterminer les mécanismes moléculaires affectées chez ce mutant, un profil d'expression génique a révélé l'induction de gènes impliqués dans la réponse au stress du réticulum endoplasmique (RE), appelée UPR, dont le rôle est de rétablir l'homéostasie du RE. Mortalin est impliqué dans le contrôle de l'UPR en interagissant avec BiP, un régulateur direct de cette voie. L'activation soutenue de l'UPR entraîne l'apoptose, ce que nous observons chez nos mutants. De plus, l'analyse du cycle cellulaire indique que la phase S est plus longue chez le mutant, suggérant que Mortalin régule le cycle cellulaire. Ainsi, l'ensemble des données suggère que Mortalin est nécessaire pour la survie des cellules au cours du développement. / The development of the head is a complex process that involves tissue interaction and cellular differentiation. Precisely how these processes are coordinated during embryogenesis remains elusive. Disruption of this coordinated development causes a wide range of malformations. In order to find new genes involved in the development of the head, a phenotype-driven ENU screen was performed. One of the mouse lines generated exhibits small pharyngeal arches (PAs), which are the main precursors of the head. Mutant embryos die around mid-gestation, most likely as a result of defective vasculature. We mapped the ENU-mediated point mutation within Mortalin. My thesis work aims to understand how Mortalin controls embryonic development. Mortalin is ubiquitously expressed before mid-gestation. Then its expression increases in the PAs and cranial ganglia. In older embryos, mortalin is expressed in muscle and nervous tissue. To determine which molecular mechanisms are affected in the mutant, gene expression profil revealed the induction of genes involved in the response to endoplasmic reticulum (ER) stress, called UPR. The role of the UPR is to restore homeostasis in the ER. I found that Mortalin regulates the UPR by interacting with BiP, a direct regulator of this pathway. Sustained activation of UPR leads to apoptosis, which is observed in our mutant. Cell cycle has been analyzed to investigate the cause of the reduced embryonic size in our mutant. The length of the S phase was found longer in the mutant, indicating that Mortalin also regulates cell cycle. All together, these data suggest that Mortalin is required for cell survival during development, in part by controlling the UPR.

Introdução: O primeiro e segundo arcos faríngeos contribuem com o desenvolvimento craniofacial e, interferências no desenvolvimento normal destas estruturas podem resultar em anomalias maxilar, mandibular e auricular. Hipoplasia de mandíbula, dermóide epibulbar e anomalias vertebrais são as características clínicas mais frequentes em associação com anomalias de orelha, resultando no grupo denominado espectro oculoauriculovertebral (EOAV). Trata-se de uma condição de etiologia heterogênea e complexa com grande variabilidade clínica. Objetivos: Investigar os sinais clínicos de uma amostra de indivíduos com diagnóstico de espectro oculoauriculovertebral; calcular a frequência dos sinais clínicos presentes nesses indivíduos e estabelecer possíveis associações entre os principais achados clínicos observados nos indivíduos da presente casuística. Indivíduos Estudados e Métodos: Estudo retrospectivo de 389 indivíduos com diagnóstico clínico de EOAV. O critério mínimo estabelecido para o estudo foi a presença de microtia isolada e/ou apêndice pré-auricular associados, ou não, à hipoplasia mandibular. Os resultados foram analisados por meio de estatística descritiva, utilizando as frequências absolutas (n) e relativas (%) e verificadas por meio do teste Qui-quadrado, com cálculo de odds ratio e intervalo de confiança. Resultados e Conclusão: Razão sexual 4M:3F; casos de recorrência, gemelaridade e consanguinidade foram observados em 15,56%, 3,85% e 2,22% da amostra, respectivamente. Intercorrências gestacionais foram relatadas por 15,09% das genitoras. Análise citogenética apontou 2 indivíduos com alteração estrutural e 2 indivíduos com alteração numérica. Frequências altas foram encontradas, principalmente, em assimetria facial (96,40%), hipoplasia do ramo mandibular (96,40%), microtia (87,40%), anomalia de coluna vertebral (77,17%), apêndice pré-auricular (60,41%), fissura Tessier 7 (31,62%), dermóide epibulbar (19,02%), fissura de lábio com ou sem palato (18,25%) e fissura de palato (15,42%). Envolvimento craniofacial bilateral foi observado em 48,82% e, unilateral, em 51,18%, estando o lado direito envolvido em 59,49% dos casos. Microtia do tipo III estava presente em 57,11% e do tipo II, em 36,01%. Dentre as anomalias estruturais de orelha média e/ou interna, o acometimento de orelha média foi o mais frequente, sendo observado em 27,91%. Em relação à deficiência auditiva, o tipo condutivo foi o mais frequente, encontrado em 70,42% das orelhas. Dentre as associações de achados clínicos realizadas, observou-se associação estatisticamente significativa entre fissura Tessier 7 e anomalia ocular (incluindo dermóide epibulbar); entre dermóide epibulbar e outras anomalias oculares; entre lateralidade da fissura de lábio com ou sem palato e acometimento craniofacial; entre anomalia de orelha média e microtia tipo III; entre anomalia de orelha interna e microtia tipo II; entre anomalia de orelha média e interna com microtia tipo III; e entre ausência de anomalia de orelha interna e/ou externa e ausência de microtia. Diante dos resultados obtidos, investigação sistemática por imagem de osso temporal, coluna vertebral, costelas e sistema cardíaco deve fazer parte do protocolo de avaliação dos indivíduos com EOAV. / Introduction: The first and second pharyngeal arches contribute to the craniofacial development, and any interference in the normal development of these structures can result in maxilar, mandibular and auricular anomalies. Mandibular hypoplasia, epibulbar dermoids, and vertebral anomalies are the most frequently clinical aspects associated with auricular anomaly, resulting in a condition defined as oculoauriculovertebral spectrum, which is a heterogeneous, variable and complex clinical condition. Objectives: Investigate the clinical findings of individuals with OAVS clinically diagnosed, calculate the frequency of the clinical findings presented in these individuals and establish possible associations among the main clinical findings observed in these series of individuals. Purpose and Methods: Retrospective study of the individuals with OAVS clinically diagnosed. The minimal criteria established for the study was the presence of isolated microtia and/or preauricular tags, associated or not associated with mandibular hypoplasia. The results were analyzed by means of descriptive analyzes, using the absolute (n), relative (%) frequency and verification by means of Qui-square test, with odds ratio calculation and trust interval. Results and Conclusion: Sex ratio 4M:3F; cases of familial recurrence, twinning and consanguinity were observed at 15.56%, 3.85% and 2.22% of the sample, respectively. Pregnancy complications were reported by 15.09% of the mothers. Cytogenetic analysis showed two individuals with structrural anomaly and two with numerical alterations. High frequences were observed mainly in facial asymmetry (96.40%), mandibular hypoplasia (96.40%), microtia (87.40%), vertebral anomalies (77.17%), preauricular tags (60.41%), Tessier 7 cleft (31.62%), epibulbar dermoid (19.02%), cleft lip and/or cleft palate (18.25%), and cleft palate (15.42%). Bilateral craniofacial involvement was observed in 48.82% and unilateral in 51.18%. The right side was involved in 59.49% of the cases. Microtia type III was observed in 57.11% of the ears and type II in 36.01%. Among the structural abnormalities of the middle and/or internal ear, the involvement of middle ear was the most frequent, being observed in 27.91%, regarding that the hearing loss of the conductive type was the most frequent, observed in 70.42% of the ears. Among the clinical associations performed, there was a statistically significant association between Tessier 7 cleft and eye abnormalities (including dermoid epibulbar); between epibulbar dermoid and other eye abnormalities; between the lateral cleft lip with or without palate and craniofacial involvement; between middle ear anomaly and microtia type III; between inner ear anomaly and microtia type II; between middle and inner ear anomaly with microtia type III; and between absence of inner and/or external ear anomaly and absence of microtia. Based on these results, systematic investigation by image of temporal bone, spine, ribs and heart system should be part of the evaluation protocol of individuals with OAVS.

Introdução: O primeiro e segundo arcos faríngeos contribuem com o desenvolvimento craniofacial e, interferências no desenvolvimento normal destas estruturas podem resultar em anomalias maxilar, mandibular e auricular. Hipoplasia de mandíbula, dermóide epibulbar e anomalias vertebrais são as características clínicas mais frequentes em associação com anomalias de orelha, resultando no grupo denominado espectro oculoauriculovertebral (EOAV). Trata-se de uma condição de etiologia heterogênea e complexa com grande variabilidade clínica. Objetivos: Investigar os sinais clínicos de uma amostra de indivíduos com diagnóstico de espectro oculoauriculovertebral; calcular a frequência dos sinais clínicos presentes nesses indivíduos e estabelecer possíveis associações entre os principais achados clínicos observados nos indivíduos da presente casuística. Indivíduos Estudados e Métodos: Estudo retrospectivo de 389 indivíduos com diagnóstico clínico de EOAV. O critério mínimo estabelecido para o estudo foi a presença de microtia isolada e/ou apêndice pré-auricular associados, ou não, à hipoplasia mandibular. Os resultados foram analisados por meio de estatística descritiva, utilizando as frequências absolutas (n) e relativas (%) e verificadas por meio do teste Qui-quadrado, com cálculo de odds ratio e intervalo de confiança. Resultados e Conclusão: Razão sexual 4M:3F; casos de recorrência, gemelaridade e consanguinidade foram observados em 15,56%, 3,85% e 2,22% da amostra, respectivamente. Intercorrências gestacionais foram relatadas por 15,09% das genitoras. Análise citogenética apontou 2 indivíduos com alteração estrutural e 2 indivíduos com alteração numérica. Frequências altas foram encontradas, principalmente, em assimetria facial (96,40%), hipoplasia do ramo mandibular (96,40%), microtia (87,40%), anomalia de coluna vertebral (77,17%), apêndice pré-auricular (60,41%), fissura Tessier 7 (31,62%), dermóide epibulbar (19,02%), fissura de lábio com ou sem palato (18,25%) e fissura de palato (15,42%). Envolvimento craniofacial bilateral foi observado em 48,82% e, unilateral, em 51,18%, estando o lado direito envolvido em 59,49% dos casos. Microtia do tipo III estava presente em 57,11% e do tipo II, em 36,01%. Dentre as anomalias estruturais de orelha média e/ou interna, o acometimento de orelha média foi o mais frequente, sendo observado em 27,91%. Em relação à deficiência auditiva, o tipo condutivo foi o mais frequente, encontrado em 70,42% das orelhas. Dentre as associações de achados clínicos realizadas, observou-se associação estatisticamente significativa entre fissura Tessier 7 e anomalia ocular (incluindo dermóide epibulbar); entre dermóide epibulbar e outras anomalias oculares; entre lateralidade da fissura de lábio com ou sem palato e acometimento craniofacial; entre anomalia de orelha média e microtia tipo III; entre anomalia de orelha interna e microtia tipo II; entre anomalia de orelha média e interna com microtia tipo III; e entre ausência de anomalia de orelha interna e/ou externa e ausência de microtia. Diante dos resultados obtidos, investigação sistemática por imagem de osso temporal, coluna vertebral, costelas e sistema cardíaco deve fazer parte do protocolo de avaliação dos indivíduos com EOAV. / Introduction: The first and second pharyngeal arches contribute to the craniofacial development, and any interference in the normal development of these structures can result in maxilar, mandibular and auricular anomalies. Mandibular hypoplasia, epibulbar dermoids, and vertebral anomalies are the most frequently clinical aspects associated with auricular anomaly, resulting in a condition defined as oculoauriculovertebral spectrum, which is a heterogeneous, variable and complex clinical condition. Objectives: Investigate the clinical findings of individuals with OAVS clinically diagnosed, calculate the frequency of the clinical findings presented in these individuals and establish possible associations among the main clinical findings observed in these series of individuals. Purpose and Methods: Retrospective study of the individuals with OAVS clinically diagnosed. The minimal criteria established for the study was the presence of isolated microtia and/or preauricular tags, associated or not associated with mandibular hypoplasia. The results were analyzed by means of descriptive analyzes, using the absolute (n), relative (%) frequency and verification by means of Qui-square test, with odds ratio calculation and trust interval. Results and Conclusion: Sex ratio 4M:3F; cases of familial recurrence, twinning and consanguinity were observed at 15.56%, 3.85% and 2.22% of the sample, respectively. Pregnancy complications were reported by 15.09% of the mothers. Cytogenetic analysis showed two individuals with structrural anomaly and two with numerical alterations. High frequences were observed mainly in facial asymmetry (96.40%), mandibular hypoplasia (96.40%), microtia (87.40%), vertebral anomalies (77.17%), preauricular tags (60.41%), Tessier 7 cleft (31.62%), epibulbar dermoid (19.02%), cleft lip and/or cleft palate (18.25%), and cleft palate (15.42%). Bilateral craniofacial involvement was observed in 48.82% and unilateral in 51.18%. The right side was involved in 59.49% of the cases. Microtia type III was observed in 57.11% of the ears and type II in 36.01%. Among the structural abnormalities of the middle and/or internal ear, the involvement of middle ear was the most frequent, being observed in 27.91%, regarding that the hearing loss of the conductive type was the most frequent, observed in 70.42% of the ears. Among the clinical associations performed, there was a statistically significant association between Tessier 7 cleft and eye abnormalities (including dermoid epibulbar); between epibulbar dermoid and other eye abnormalities; between the lateral cleft lip with or without palate and craniofacial involvement; between middle ear anomaly and microtia type III; between inner ear anomaly and microtia type II; between middle and inner ear anomaly with microtia type III; and between absence of inner and/or external ear anomaly and absence of microtia. Based on these results, systematic investigation by image of temporal bone, spine, ribs and heart system should be part of the evaluation protocol of individuals with OAVS.