The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation

Abstract

BMPs play multiple roles in development and BMP signaling is essential for lens formation. However, the mechanisms by which BMP receptors function in vertebrate development are incompletely understood. To determine the downstream effectors of BMP signaling and their functions in the ectoderm that will form the lens, we deleted the genes encoding the type I BMP receptors, Bmpr1a and Acvr1, and the canonical transducers of BMP signaling, Smad4, Smad1 and Smad5. Bmpr1a and Acvr1 regulated cell survival and proliferation, respectively. Absence of both receptors interfered with the expression of proteins involved in normal lens development and prevented lens formation, demonstrating that BMPs induce lens formation by acting directly on the prospective lens ectoderm. Remarkably, the canonical Smad signaling pathway was not needed for most of these processes. Lens formation, placode cell proliferation, the expression of FoxE3, a lens-specific transcription factor, and the lens protein, αA-crystallin were regulated by BMP receptors in a Smad-independent manner. Placode cell survival was promoted by R-Smad signaling, but in a manner that did not involve Smad4. Of the responses tested, only maintaining a high level of Sox2 protein, a transcription factor expressed early in placode formation, required the canonical Smad pathway. A key function of Smad-independent BMP receptor signaling may be reorganization of actin cytoskeleton to drive lens invagination.

MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

“…The preliminary results indicate that cell proliferation before E11.5 is likely to be mediated by MAPK1/3-independent pathways (data not shown). It has been shown that BMP/activinactivated signals are essential for cell proliferation during early lens development (Rajagopal et al, 2009). Additionally, our results indicated that loss of both MAPK1 and MAPK3 in the lens drastically reduced cell proliferation throughout the entire epithelial layer at E14.5 (Fig.…”

An Atypical Canonical Bone Morphogenetic Protein (BMP) Signaling Pathway Regulates Msh Homeobox 1 (Msx1) Expression during Odontogenesis

“…During nervous system development, conditional inactivation of Smad1 and Smad5 resulted in cerebellar hypoplasia, reduced granule cell numbers, and disorganized Purkinje neuron migration during embryonic development, whereas conditional inactivation of Smad4 produced only very mild cerebellar defects (10). Furthermore, during lens development, cell death occurred associated with inactivation of Smad1/5, but not with inactivation of Smad4 (12). In addition, Smad1 and Smad5 have been proven essential for bone development, but inactivation of Smad4 led to only minor bone defects (42).…”

Villification in the mouse: Bmp signals control intestinal villus patterning

“…Studies in other systems have shown that inhibition of Bmp signaling in the epithelium causes cells to shorten and become columnar or cuboidal (Eom et al, 2011;Gibson and Perrimon, 2005;Rajagopal et al, 2009;Shen and Dahmann, 2005). However, dorsomorphin treatment does not cause widespread columnar conversion; epithelium above the merged clusters is columnar, while epithelium between these clusters remains pseudostratified (Fig.…”