Craniofacial abnormalities are the most common human birth defects, and yet little is known about the developmental basis that leads to mispatterning of the face. Several studies have Identified factors involved in patterning the lower (ventral) face;however, less is known about the dorsal (upper) face. In humans, mutations in Jagged and Notch have been linked to Alagille syndrome, whereas aberrant Fgf signaling results in Crouzon syndrome. As similar facial defects are observed in both Alagille and Crouzon, Notch and Fgf may be involved in a common pathway that patterns the facial skeleton. In this proposal, I investigate a novel role of Jagged-Notch and Fgf signaling in zebrafish involved in promoting dorsal facial identity. In my preliminary data, Jagged-Notch signaling promotes dorsal facial identity by repressing ventral gene expression in skeletal precursors;however, the molecular mechanism of how Notch promotes dorsal remains unknown. Thus in the first aim, I propose a model where dorsal facial identity is specified by a propagating Notch signaling wave that originates in the dorsal domain. Using a transgenic Notch reporter and high-resolution imaging, I will capture Notch activation in real time during patterning stages. In the second aim, I propose experiments that build on my initial findings that Fgf signaling also promotes dorsal identity. By using transgenic fish, in which Fgf signaling is upregulated or inhibited at specific times of development, I will determine if Fgf signaling uses similar molecular mechanisms as Notch to promote dorsal identity. In the third aim, I will test how Jagged-Notch and Fgf signaling pathways are integrated to actively promote dorsal facial identity. Here, I propose a linear and a parallel model of signal integration. In the linear model, Fgf signaling activates the Notch pathway by controlling jagib expression. In the parallel model, Fgf and Notch independently activate the same downstream targets involved in dorsal facial patterning. To test this, I will use combinations of mutants and transgenics with altered Notch and Fgf signaling to determine how these two pathways are integrated. The goal of this proposal is to investigate a novel role of Jagged-Notch and Fgf signaling in patterning the vertebrate upper face. As mutations in Jagged 1 and the Fgf receptor 2 have been linked to craniofacial defects in Alagille and Crouzon syndrome, my work in zebrafish will reveal the developmental basis by which disruption of these pathways results in facial defects in humans.
|Alexander, Courtney; Zuniga, Elizabeth; Blitz, Ira L et al. (2011) Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton. Development 138:5135-46|
|Zuniga, Elizabeth; Rippen, Marie; Alexander, Courtney et al. (2011) Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton. Development 138:5147-56|