The Lim domain binding proteins (Ldbs) are key cofactor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation throughout the CNS. Here, using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both genes. We show that Ldb1 interacts with Lhx2 in the embryonic retina and that both Ldb1 and Ldb2, probably functioning with Lhx2 in a complex, play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the homeodomain factors Vsx2 and Rax, as well as components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2 mediated complex, is essential for generation of early-born photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early and late-stage RPCs and in Muller glia. In contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. These findings uncover an intricate regulatory network mediated by Ldb1 and Ldb2 that promotes RPC proliferation and multipotency, and also controls specification of the major cell types of the mammalian retina.
- Received August 13, 2015.
- Accepted September 20, 2016.