Investigating the Role of BMP Antagonists in Vertebrate Eye Development

• Author / Creator

  Weekes, Jennifer Michelle

• Vertebrate eye development is a dynamic process that couples morphogenesis, migration of extraocular periocular mesenchyme (POM) cells to the eye, and retinal patterning along the nasotemporal and dorsoventral (DV) axes. Aberrant patterning during ocular development often results in defects including microphthalmia (small eyes), anophthalmia (no eyes), and coloboma (MAC). Coloboma occurs when the choroid fissure, a transient opening needed for vascularization and optic nerve formation, fails to close later in development. The eye is patterned in much the same way that the body axes are patterned via morphogen gradients established by the spatially restricted expression of diffusible extracellular molecules. Antagonists can further modify and shape morphogen gradients by establishing an opposing gradient. How these morphogen gradients work during eye patterning has been thoroughly studied in NT patterning, but much less is known about DV retinal patterning.
  The dorsal retina is specified by BMP signaling restricted to the dorsal eye. Loss of BMP signaling results in a ventralized retina and ventral eye defects including coloboma. The ventral eye defects that occur with aberrant dorsoventral patterning suggest that dorsalizing and ventralizing signals must be balanced for proper patterning and structure; however, our knowledge of ventral retinal patterning remains incomplete. Evidence in chick indicates that BMP antagonists restricted to the ventral retina specify ventral retinal fate, but the BMP antagonists characterized appear to be chick specific, and to date no BMP antagonist restricted to the ventral eye in other vertebrates has been characterized.
  This work has identified three putative BMP inhibitors restricted to the ventral retina or surrounding cells during eye development: SPARC-related modular calcium binding 1 (Smoc1), Smoc2, and Gremlin2b (Grem2b). Expression of smoc1 and smoc2 was found to be restricted to the ventral retina while grem2b is expressed in what appears to be a novel subpopulation of POM cells that migrate exclusively to the ventral retina and choroid fissure. Reducing levels of these three proteins using antisense morpholino oligonucleotides resulted in microphthalmia, suggesting that inhibition of BMP signaling is necessary to regulate ocular size. Further loss of function studies revealed that Grem2b regulates BMP signaling in the dorsal eye while Smoc1 regulates BMP signaling in the dorsal eye and choroid fissure, indicating that Smoc1 could be involved in choroid fissure closure or vascularization. Reducing Smoc1 protein levels showed that Smoc1 is involved in DV retinal patterning, but likely during maintenance of DV patterning rather than initial specification. Together, these results provide an initial characterization of three BMP inhibitors during early vertebrate eye development and have surprisingly revealed that inhibition of BMP signaling occurs in the ventral retina although the source of these BMP signals remains unknown.

• Subjects / Keywords

  • MAC
  • BMP
  • Retinotectal
  • Coloboma
  • Retinoic acid
  • Aldehyde dehydrogenase
  • Gdf6
  • Gremlin
  • Eye
  • Zebrafish
  • Smoc1
  • POM
  • Microphthalmia
  • Bone morphogenetic protein
  • Grem2b
  • Periocular mesenchyme
  • Aldh1a3
  • Smoc
  • Choroid fissure
  • Patterning
  • Grem2
  • Smoc2

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R36M33F3K

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.