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The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development

Li, Chaochang
http://orcid.org/0000-0002-1842-2004
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular and 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.
Rulang Jiang, Ph.D. (Committee Chair)
Stephan Glasser, Ph.D. (Committee Member)
Joo-Seop Park, Ph.D. (Committee Member)
S. Steven Potter, Ph.D. (Committee Member)
Rolf Stottmann, PhD (Committee Member)
184 p.
Developmental Biology

Recommended Citations

Citations

  • Li, C. (2020). The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049

    APA Style (7th edition)

  • Li, Chaochang. The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049.

    MLA Style (8th edition)

  • Li, Chaochang. "The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583152487076049

    Chicago Manual of Style (17th edition)

ucin1583152487076049
211
© 2020, some rights reserved.Creative Commons License The roles of Six1, Six2 and Pax9 transcription factors in craniofacial development by Chaochang Li is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.