Item Details

The role of homeobox transcription factor six3 in vertebrate eye development

Manohar, Sumanth
Format
Thesis/Dissertation; Online
Author
Manohar, Sumanth
Advisor
Grainger, Robert
Abstract
Six3, a homolog of Drosophila optix, is a homeobox-containing transcription factor critical for early anterior patterning and forebrain/eye formation. In humans, haploinsufficiency of SIX3 has been associated with holoprosencephaly. Six3 is a key component of the gene regulatory network (GRN) controlling eye formation along with genes such as Pax6, Rax, Lhx2 and Otx2. However, the position of Six3 in the eye GRN is unclear, in part because mouse homozygous Six3 mutants are headless and conditional mutants targeting Six3 make definitive epistatic relationships difficult to determine. We have generated a six3 mutant line in Xenopus tropicalis that has been uniquely valuable in revealing a central role for six3 in regulating eye development. In contrast to mouse, Xenopus six3 mutants retain a head but have malformed eyes with missing or undifferentiated lenses and a disorganized retina. We describe several key findings. 1) six3 and pax6 are regulated independently of each other in the lens ectoderm and early lens induction is not affected by the loss of six3 while later phases of lens induction are severely impacted in the mutant. 2) six3 activity is independent and additive to the related eye gene six6 in eye formation. 3) The missing and defective lenses in the six3 mutants are primarily due to its non-autonomous function mediated by the optic vesicle. 4) Our data here supports an essential role for the mab21 genes in regulating lens and eye formation downstream of six3. 5) six3 regulates lens and retina formation by impinging on the BMP, Notch and Wnt signaling pathways. 6) Our preliminary evidence also supports an important role for six3 in patterning the neuroretina. Taken together, our findings present a new perspective on the eye GRN with six3 at the top of this gene hierarchy in parallel with pax6 and likely in concert with other eye field transcription factors regulating lens and retina formation.
Language
English
Published
University of Virginia, Biology - Graduate School of Arts and Sciences, PHD (Doctor of Philosophy), 2019
Published Date
2019-11-30
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
Logo for In CopyrightIn Copyright

Availability

Read Online