EYEDEVELOPMENT

Molecular genetic regulation of eye field development

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Anophthalmia and microphthalmia, birth defects that are important causes of childhood blindness, often arise as a result of abnormal development of eye progenitors in the eye field during early embryogenesis. The molecular genetic mechanisms that underlie eye progenitor development in the eye field are not well understood. This proposal aims to identify cellular, molecular and genetic mechanisms of eye progenitor development during the eye field stage using zebrafish as a model organism. We will focus on regulation of eye field development by the transcription factor Six3, whose loss of function has been shown to cause anophthalmia or microphthalmia in humans and several genetic model organisms including zebrafish. We will use a combination of in vivo studies with genetic and molecular approaches toward two specific objectives: first, we will identify cellular mechanisms underlying loss of eye progenitors during eye field stage in Six3-deficient zebrafish embryos, which exhibit anophthalmia or microphthalmia. This will be achieved by following eye progenitors in live Six3-deficient embryos and determining their fates. Subsequent analyses will address the molecular mechanisms that lead to these fates. The second specific objective will identify protein-coding genes and miRNAs that are important for eye field development, with focus on downstream targets of Six3. This will be achieved using a transgenic approach to isolate eye field cells from wild-type and Six3-deficient embryos and identify protein-coding genes and miRNAs that are specifically expressed in the eye field and whose expression is affected by the loss of Six3 function. Together, these studies will lead to better understanding of the genetic network that underlies early eye development. Such knowledge is necessary for improving the ability to provide genetic counseling and may also help in prevention of severe eye malformation.'

Introduzione (Teaser)

A number of disorders emerge due to abnormalities during development. A European study wished to address blindness by focusing on the mechanisms that govern eye development.

Descrizione progetto (Article)

Childhood blindness is very often a result of birth defects such as anophthalmia, microphthalmia and coloboma. These conditions arise as a result of abnormal development of progenitors in the eye during early embryogenesis.

The EU-funded 'Molecular genetic regulation of eye field development' (EYEDEVELOPMENT) project used zebrafish as a model organism to study eye development. The work focused on the SIX3 family of transcription factors and particularly embryos lacking both SIX3b and SIX7 proteins. Scientists wanted to investigate why eye development fails when progenitors form normally.

To identify the molecular and cellular mechanisms which explain this phenomenon, they isolated eye progenitors and compared their gene expression profiles. They excluded mutant progenitors that underwent p53-mediated cell death or presented an increased Wnt signalling pattern. Further work is expected to determine which other death-related mechanisms are in place.

Additional mutant embryos lacking both SIX3a and SIX3b were generated. These demonstrated abnormal light passage through the lens of the eye associated with abnormalities in the optic nerve axon pathfinding. The observed defects could stem from retinal ganglion cells or could be attributed to abnormal signals from the environment. Molecular analysis unveiled reduced expression of certain chemokines whose precise role in axon guidance remains to be determined.

Collectively, the results of the EYEDEVELOPMENT study indicate a novel role of SIX3 in optic nerve development and open up new avenues of research. Delineating the mechanisms which drive eye progenitor and optic nerve development will contribute to the development of cell replacement therapies in the future.