The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development
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University of Cincinnati / OhioLINK
2020
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15831524870760492021-08-03T07:13:47Z The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development Li, Chaochang Developmental Biology Craniofacial development is a highly dynamic and complex multi-step process, highly regulated by a genetically programmed molecular network involving multiple signaling pathways and transcription factors. We investigated the function of Pax9, Six1 and Six2 transcription factors in the development of several craniofacial structures. Heterozygous deletions of SIX2 have recently been associated with frontonasal dysplasia (FND), characterized by ocular hypertelorism, a large anterior fontanelle, ptosis, and conductive hearing loss. However, mice with targeted disruptions of Six2 did not completely recapitulate the FND phenotypes. Six2 is a member of the sine oculis family of transcription factors and is structurally most closely related to Six1. In Chapter 2, we show that Six1 and Six2 exhibit overlapping expression patterns in the developing frontonasal and maxillary processes and function partly redundantly to control multiple processes during craniofacial development.Six1 is expressed in various tissues during development and perform crucial functions in differentiation, morphogenesis and organogenesis. Besides severe frontonasal defects including midline facial clefting shown in Six1-/-Six2-/- mice, we also noticed that Six1-/- mice exhibited distal mandibular defects including absence of mandibular incisors. Previous studies have shown that Six1 is required to regulate the expression of several signaling molecules in the mandibular epithelium, such as Fgf8 and Edn1. However, the cell-autonomous function of Six1 in the neural crest-derived mandibular mesenchyme remained unknown. In Chapter 3, we uncover the roles of Six1 in cranial neural crest-derived mandibular mesenchyme in the development of the mandible and incisors.Both Six1 and Six2 are expressed in multiple cell lineages, including mandibular and palatal epithelium and mesenchyme, ectodermal placode derivatives, cranial mesoderm, and neural crest-derived frontonasal, maxillary, and mandibular mesenchyme, during craniofacial development. In Chapter 4, we report the generation of mice carrying insertions of a pair of loxP sites flanking exon-1 of the Six2 gene (Six2f allele) through a two-step CRISPR/cas9-mediated genome editing, and demonstrate that the Six2f allele was functionally normal and allowed Cre-mediated tissue-specific functional analysis. Furthermore, we show that Six2f/f;Wnt1-Cre mice recapitulated the cranial base developmental defects but not neonatal lethality of Six2-/- mice. The Six2f/f mice enable unprecedented systematic investigation of cell type- and stage-specific Six2 function in development and disease.Cleft palate is one of the major birth defects in humans. Palatogenesis is regulated by a genetically programmed molecular network consisting of multiple signaling pathways and transcription factors. Pax9, a transcription factor expressed in the developing palatal mesenchyme, is a key regulator of palatogenesis. In Chapter 5, we report that Wnt signaling plays an important role in the Pax9-mediated regulation of palate development. We demonstrate that enhancing Wnt signaling either pharmacologically or genetically partly rescued palate morphogenesis in Pax9 mutant mice. Our data provide new insights into the molecular mechanisms of palatogenesis. 2020-06-02 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Developmental Biology |
| spellingShingle |
Developmental Biology Li, Chaochang The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| author |
Li, Chaochang |
| author_facet |
Li, Chaochang |
| author_sort |
Li, Chaochang |
| title |
The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| title_short |
The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| title_full |
The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| title_fullStr |
The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| title_full_unstemmed |
The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development |
| title_sort |
roles of six1, six2 and pax9 transcription factors in craniofacial development |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2020 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049 |
| work_keys_str_mv |
AT lichaochang therolesofsix1six2andpax9transcriptionfactorsincraniofacialdevelopment AT lichaochang rolesofsix1six2andpax9transcriptionfactorsincraniofacialdevelopment |
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