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The negative regulatory Spred1 and Spred2 proteins are required for lens and eye morphogenesis
Fatima Wazin1, Frank J Lovicu1
1Discipline of Anatomy and Histology, School of Medical Science, The University of Sydney, NSW, Australia and Save Sight Institute, The University of Sydney, NSW, Australia.
Abstract:
The transparent and refractive properties of the ocular lens are dependent on its precise cellular structure, supported by the regulation of lens cellular processes of proliferation and differentiation that are essential throughout life. The ERK/MAPK-signalling pathway plays a crucial role in regulating lens cell proliferation and differentiation, and in turn is regulated by inhibitory molecules including the Spred family of proteins to modulate and attenuate the impact of growth factor stimulation. Given Spreds are strongly and distinctly expressed in lens, along with their established inhibitory role in a range of different tissues, we investigated the role these antagonists play in regulating lens cell proliferation and differentiation, and their contribution to lens structure and growth. Using established mice lines deficient for either or both Spred 1 and Spred 2, we demonstrate their role in regulating lens development by negatively regulating ERK1/2 activity. Mice deficient for both Spred 1 and Spred 2 have impaired lens and eye development, displaying irregular lens epithelial and fibre cell activity as a result of increased levels of phosphorylated ERK1/2. While Spred 1 and Spred 2 do not appear to be necessary for induction and early stages of lens morphogenesis (prior to E11.5), nor for the formation of the primary fibre cells, they are required for the continuous embryonic growth and differentiation of the lens.
Insights
Spred 1 and Spred 2 proteins are crucial for regulating ocular lens cell growth and differentiation by inhibiting the ERK/MAPK pathway. Their absence impairs lens development and structure.
Area of Science:
- Ophthalmology
- Developmental Biology
- Cell Signaling
Background:
- Ocular lens transparency relies on cellular structure and regulated cell proliferation/differentiation.
- The ERK/MAPK pathway controls lens cell activity, modulated by inhibitory Spred proteins.
- Spred proteins are highly expressed in the lens, suggesting a key regulatory role.
Purpose of the Study:
- Investigate the function of Spred 1 and Spred 2 in regulating lens cell proliferation and differentiation.
- Determine the contribution of Spreds to lens structure, growth, and development.
- Elucidate the role of Spreds in modulating ERK/MAPK signaling within the lens.
Main Methods:
- Utilized Spred 1 and Spred 2 deficient mouse lines.
- Analyzed lens and eye development in these mouse models.
- Assessed levels of phosphorylated ERK1/2 (pERK1/2) to evaluate pathway activity.
Main Results:
- Spred 1 and Spred 2 negatively regulate ERK1/2 activity in the developing lens.
- Mice lacking both Spred 1 and Spred 2 exhibit impaired lens and eye development.
- These mice show irregular lens epithelial and fiber cell activity due to elevated pERK1/2.
- Spreds are essential for continuous embryonic lens growth and differentiation after initial morphogenesis.
Conclusions:
- Spred 1 and Spred 2 are critical negative regulators of ERK/MAPK signaling in the ocular lens.
- These proteins are indispensable for normal embryonic lens growth, differentiation, and overall eye development.
- Disruption of Spred function leads to developmental abnormalities in the lens.
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