SMAD7 deficiency stimulates Müller progenitor cell proliferation during the development of the mammalian retina

Abstract

The transforming growth factor-β (TGF-β) pathway contributes to maintain the quiescence of adult neural stem and progenitor cells in the brain. In the retina, Müller cells are discussed to represent a glial cell population with progenitor-like characteristics. Here, we aimed to investigate if elevated TGF-β signaling modulates the proliferation of Müller cells during retinal development. We generated mutant mice with a systemic, heterozygous up-regulation of TGF-β signaling by deleting its inhibitor SMAD7. We investigated apoptosis, proliferation, and differentiation of Müller cells in the developing retina. We show that a heterozygous deletion of SMAD7 results in an increased proliferation of Müller cell progenitors in the central retina at postnatal day 4, the time window when Müller cells differentiate in the mouse retina. This in turn results in a thickened retina and inner nuclear layer and a higher number of differentiated Müller cells in the more developed retina. Müller cells in mutant mice contain higher amounts of nestin than those of control animals which indicates that the increase in TGF-β signaling activity during retinal development contribute to maintain some progenitor-like characteristics in Müller cells even after their differentiation period. We conclude that TGF-β signaling influences Müller cell proliferation and differentiation during retinal development.

Transcriptional Profiling Identifies Upregulation of Neuroprotective Pathways in Retinitis Pigmentosa

“…The enucleated eyes were fixed for 24 h in 2.5% paraformaldehyde (PFA)/2.5% glutaraldehyde in sodium cacodylate buffer and processed as described previously [60]. Then, 1 µm thick semithin meridional sections were cut and stained according to Richardson [61].…”

Deletion of Endothelial Transforming Growth Factor–β Signaling Leads to Choroidal Neovascularization

“…Eyes were enucleated, fixed for 24 hours in 2% PFA/2.5% glutaraldehyde, 34 and embedded in Epon (Serva), as described elsewhere. 35,36 Semithin meridional sections (1 mm thick) were cut through the eyes and stained, according to the method of Richardson et al 37 The sections were analyzed on an Axio Imager Z1 microscope (Carl Zeiss) using Axiovision software version 4.8 (Carl Zeiss). Ultrathin sections were processed according to protocols published previously, 38,39 stained with uranyl acetate and lead citrate, and analyzed on a transmission electron microscope (Libra; Carl Zeiss).…”

TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

“…In the retina, TGFβR1 and -2 are expressed in neurons and Müller cells, vascular cells, and the retinal pigment epithelium [167,168] (www.proteinatlas.org, accessed 7 February 2021). Canonical TGFβ signaling plays essential roles in cell growth, migration, proliferation and cell death, both during ocular development as well as in tissue homeostasis during adulthood [34,37,42,[169][170][171][172][173][174][175][176]. TGFβ2deficient mice exhibit abnormal ocular morphogenesis with a thin corneal stroma, absence of corneal endothelium, and fusion of the cornea with the lens [37,176].…”

“…The transforming growth factor (TGF) β family constitutes a superfamily of cytokines with a broad variety of different cellular functions such as cell development, differentiation and survival, morphogenesis and angiogenesis, tissue homeostasis, inflammation and remodeling [32][33][34][35][36][37][38][39][40][41][42]. The TGFβ superfamily includes TGFβs (TGFβ1, -β2, and -β3), bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activins, inhibins, nodal, and anti-Mullerian hormone proteins [43,44].…”