Roles for Transcription Factors and Signaling Pathways in Hindbrain Segmentation and Ventricle Morphogenesis

  • Author / Creator
    Selland, Lyndsay
  • During development, expression and localization of transcription factors and transcriptional co-regulators must be tightly controlled, and in turn they are required to regulate cellular identity and cellular processes. Often this involves complex interactions with signaling pathways. We are interested in the role of transcription factors and co-regulators in regulating hindbrain segmentation and ventricle morphogenesis.
    Previous research has suggested that paralog group (PG) 1 hox genes may play a central role in establishing overall hindbrain identity, as the loss of pbx cofactors results in a loss of hindbrain identity. We find that hoxb1a regulates r4 identity, while hoxb1b is required for regulation of segmentation and rhombomere size. The loss of both hoxb1b and pbx4 is required to revert the hindbrain to the r1 ground state identity. Pbx genes regulate RA signaling through regulation of RA synthesis, while hoxb1b is required for regulation of FGF signaling and together they establish overall hindbrain identity. This suggests a central role for pbx, as more than just a cofactor to PG1 hox genes.
    Although previous research has identified processes involved in the development of the hindbrain ventricle, we wished to identify genes and signaling pathways involved in this process. The transcriptional co-regulator taz (WW domain containing transcription regulator 1; wwtr1) is localized to rhombomere boundaries, and taz mutants have disruptions in ventricle morphogenesis, causing midline separation defects and the mislocalization of apicobasal polarity components and mild reductions in cell proliferation. Previous work has shown that Taz is incorporated into the β-catenin destruction complex in the absence of Wnt ligands, where it recruits the E3 ubiquitin ligase β-TrCP (beta-transducin repeat containing E3 ubiquitin protein ligase), resulting in degradation of both β-catenin and Taz. Our results support roles for Wnt ligands at rhombomere boundaries in regulating the stabilization of Taz protein at rhombomere boundaries. Furthermore both β–catenin and Taz are required transcriptional regulators for ventricle development. Taz also regulates the expression of rfng (RFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase) and wnt1 (wingless-type MMTV integration site family, member 1) at rhombomere boundaries, suggesting roles for Taz in mediating Notch signalling in ventricle development. Although disruption of Notch signalling does affect the size of the hindbrain ventricle, loss of taz does not appear to affect Notch mediated patterning of neurogenesis. Together this supports roles for Taz as a component of the Wnt/β-catenin signaling pathway and in the regulation of Notch signaling at rhombomere boundaries, and we provide evidence that these interactions are involved in hindbrain ventricle morphogenesis.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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