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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2009)

MEF2 transcription factors are well-established regulators of cardiac and skeletal muscle development. We have identified a novel role for MEF2C in the neural crest where its function is required for craniofacial development. Conditional inactivation of Mef2c in the neural crest results in severe defects in multiple bones of the craniofacial skeleton, leading to neonatal lethality due to upper airway obstruction.

Here I have identified the molecular pathways involving MEF2C during craniofacial development. I show that MEF2C directly regulates Dlx5 and Dlx6 expression in the craniofacial mesenchyme through a novel branchial arch-specific enhancer in the Dlx5/6 locus. In addition, MEF2C and Dlx5 transcriptionally synergize on the Dlx5/6 enhancer, suggesting that Dlx5 is not only a downstream target but also a cofactor of MEF2C during craniofacial development. I present strong evidence to show that MEF2C and Dlx5 can physically interact through their DNA binding domains. In addition to this transcriptional synergy and physical association, MEF2C and Dlx5 genetically interact. Heterozygosity at either locus (Dlx5/6+/- or Mef2c+/-) results in viable mice with no obvious phenotype, but heterozygosity at both loci (Dlx5/6+/-;Mef2c+/-) results in perinatal lethality. Dlx5/6+/-;Mef2c+/- mice exhibit a significant cleft of the posterior palate, caused due to a delay in the elevation and closure of palatal shelves, suggesting that MEF2C and Dlx5/6 may coregulate palatogenesis. Preliminary evidence suggests that this palate defect may be due to a delay or defect in osteogenic differentiation within the palatal shelves.

In addition to craniofacial defects, neural crest-specific knockouts of Mef2c also show reduced expression of several melanocyte genes during development, and a significant reduction in the number of melanocytes at birth. We have strong evidence to suggest that

MEF2C is a direct transcriptional target and cofactor of Sox10 in the melanocyte lineage.

Taken together, the results presented in this thesis identify two neural crest lineages, the craniofacial skeleton and melanocytes, in which MEF2C cooperates with lineage-specific transcription factors to potentiate cell fate decisions. These data also lend significant insight into our understanding of the transcriptional complexes and signaling pathways facilitating the development of these lineages.

    Cover page: Transcriptional Control of Neural Crest Development by MEF2C
    • Article
    Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health, Volume 24, Issue 2.1 (2023)
      Cover page: The Utility of the Columbia-Suicide Severity Rating Scale in Determining a Patient‚ Imminent Risk for Suicide in the Emergency DepartmentCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2010)
      Anophthalmia and microphthalmia are important birth defects, but their pathogenesis remains incompletely understood. We studied a patient with severe unilateral microphthalmia who had a 2.7 Mb deletion at chromosome 18q22.1 that was inherited from his mother. In-situ hybridization showed that one of the deleted genes, TMX3, was expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye. We re-sequenced TMX3 in 162 patients with anophthalmia or microphthalmia, and found two missense substitutions in unrelated patients: c.116G>A, predicting p.Arg39Gln, in a male with unilateral microphthalmia and retinal coloboma, and c.322G>A, predicting p.Asp108Asn, in a female with unilateral microphthalmia and severe micrognathia. We used two antisense morpholinos targeted against the zebrafish TMX3 orthologue, zgc:110025, to examine the effects of reduced gene expression in eye development. We noted that the morphant larvae resulting from both morpholinos had significantly smaller eye sizes and reduced labeling with islet-1 antibody directed against retinal ganglion cells at 2 days post fertilization. Co-injection of human wild type TMX3 mRNA rescued the small eye phenotype obtained with both morpholinos, whereas co-injection of human TMX3(p.Arg39Gln) mutant mRNA, analogous to the mutation in the patient with microphthalmia and coloboma, did not rescue the small eye phenotype. Our results show that haploinsufficiency for TMX3 results in a small eye phenotype and represents a novel genetic cause of microphthalmia and coloboma. Future experiments to determine if other thioredoxins are important in eye morphogenesis and to clarify the mechanism of function of TMX3 in eye development are warranted.
        Cover page: A Male with Unilateral Microphthalmia Reveals a Role for TMX3 in Eye Development
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