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First published online June 8, 2005
doi: 10.1242/10.1242/dev.01882

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Retinal neurons regulate proliferation of postnatal progenitors and Müller glia in the rat retina via TGFß signaling

Neurobiology and Behavior Program, Department of Biological Structure, 357420 Health Sciences Center, University of Washington, School of Medicine, Seattle, WA 98195, USA

^* Author for correspondence (e-mail: tomreh{at}u.washington.edu)

Accepted 27 April 2005

The number of proliferating cells in the rodent retina declines dramatically after birth. To determine if extrinsic factors in the retinal micro-environment are responsible for this decline in proliferation, we established cultures of retinal progenitors or Müller glia, and added dissociated retinal neurons from older retinas. The older cells inhibited proliferation of progenitor cells and Müller glia. When these experiments were performed in the presence of TGFßRII-Fc fusion protein, an inhibitor of TGFß signaling, proliferation was restored. This suggests a retina-derived TGFß signal is responsible for the developmental decline in retinal proliferation. TGFß receptors I and II are expressed in the retina and are located in nestin-positive progenitors early in development and glast-positive Müller glia later in development. RT-PCR and immunofluorescence data show TGFß2 is the most highly expressed TGFß ligand in the postnatal retina, and it is expressed by inner retinal neurons. Addition of either TGFß1 or TGFß2 to postnatal day 4 retinas significantly inhibited progenitor proliferation, while treatment of explanted postnatal day 6 retinas with TGFß signaling inhibitors resulted in increased proliferation. Last, we tested the effects of TGFß in vivo by injections of TGFß signaling inhibitors: when TGFß signaling is inhibited at postnatal day 5.5, proliferation is increased in the central retina; and when co-injected with EGF at postnatal day 10, TGFß inhibitors stimulate Müller glial proliferation. In sum, these results show that retinal neurons produce a cytostatic TGFß signal that maintains mitotic quiescence in the postnatal rat retina.

Key words: TGFß, Müller glia, Proliferation, Progenitors, Retinogenesis, Cytostasis, Rat

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