Functions of the type 1 BMP receptor Acvr1 (Alk2) in lens development: cell proliferation, terminal differentiation, and survival.
OBJECTIVE
Bone morphogenetic protein (BMP) signaling is essential for the induction and subsequent development of the lens. The purpose of this study was to analyze the function(s) of the type 1 BMP receptor, Acvr1, in lens development.


METHODS
Acvr1 was deleted from the surface ectoderm of mouse embryos on embryonic day 9 using the Cre-loxP METHOD: Cell proliferation, cell cycle exit, and apoptosis were measured in tissue sections by immunohistochemistry, immunofluorescence, and TUNEL staining.


RESULTS
Lenses formed in the absence of Acvr1. However, Acvr1(CKO) (conditional knockout) lenses were small. Acvr1 signaling promoted proliferation at early stages of lens formation but inhibited proliferation at later stages. Inhibition of cell proliferation by Acvr1 was necessary for the proper regionalization of the lens epithelium and promoted the withdrawal of lens fiber cells from the cell cycle. In spite of the failure of all Acvr1(CKO) fiber cells to withdraw from the cell cycle, they expressed proteins characteristic of differentiated fiber cells. Although the stimulation of proliferation was Smad independent, the ability of Acvr1 to promote cell cycle exit later in development depended on classical R-Smad-Smad4 signaling. Loss of Acvr1 led to an increase in apoptosis of lens epithelial and fiber cells. Increased cell death, together with the initial decrease in proliferation, appeared to account for the smaller sizes of the Acvr1(CKO) lenses.


CONCLUSIONS
This study revealed a novel switch in the functions of Acvr1 in regulating lens cell proliferation. Previously unknown functions mediated by this receptor included regionalization of the lens epithelium and cell cycle exit during fiber cell differentiation.
Department of Ophthalmology and Visual Sciences, Washington University, St Louis, Missouri 63110, USA. rajagopal@vision.wustl.edu
Ramya
R
Rajagopal
Lisa K
LK
Dattilo
Vesa
V
Kaartinen
Chu-Xia
CX
Deng
Lieve
L
Umans
An
A
Zwijsen
Anita B
AB
Roberts
Erwin P
EP
Bottinger
David C
DC
Beebe
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D007908:Lens, Crystalline / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D015398:Signal Transduction
D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse