Follistatin modulates a BMP autoregulatory loop to control the size and patterning of sensory domains in the developing tongue

Abstract

The regenerative capacity of many placode-derived epithelial structures makes them of interest for understanding the molecular control of epithelial stem cells and their niches. Here, we investigate the interaction between the developing epithelium and its surrounding mesenchyme in one such system, the taste papillae and sensory taste buds of the mouse tongue. We identify follistatin (FST) as a mesenchymal factor that controls size, patterning and gustatory cell differentiation in developing taste papillae. FST limits expansion and differentiation of Sox2-expressing taste progenitor cells and negatively regulates the development of taste papillae in the lingual epithelium: in Fst -/-tongue, there is both ectopic development of Sox2-expressing taste progenitors and accelerated differentiation of gustatory cells. Loss of Fst leads to elevated activity and increased expression of epithelial Bmp7; the latter effect is consistent with BMP7 positive autoregulation, a phenomenon we demonstrate directly. We show that FST and BMP7 influence the activity and expression of other signaling systems that play important roles in the development of taste papillae and taste buds. In addition, using computational modeling, we show how aberrations in taste papillae patterning in Fst -/-mice could result from disruption of an FST-BMP7 regulatory circuit that normally suppresses noise in a process based on diffusion-driven instability. Because inactivation of Bmp7 rescues many of the defects observed in Fst -/-tongue, we conclude that interactions between mesenchyme-derived FST and epithelial BMP7 play a central role in the morphogenesis, innervation and maintenance of taste buds and their stem/progenitor cells.

Coevolutionary patterning of teeth and taste buds

“…Zhou et al (53) report that culture of rat tongues with purified BMPs or the antagonist Noggin at E13 results in increased numbers of taste papillae, but that treatment at E14 with BMPs decreases papillae, whereas Noggin treatment increases them. Interestingly, genetic ablation of Follistatin increases BMP signal in the mouse tongue and gives rise to ectopic posterior papillae that express Sox2 and Foxa2, but which appear to invaginate rather than evaginate like typical taste buds (54). Overall, teeth and taste buds share gene synexpression and a deep molecular homology (12).…”

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

“…Moreover, we found follistatin selectively suppressed activin/TGF-␤ signaling in mouse hippocampus. It has been shown that TGF-␤ family signaling regulates other family members' transcript levels by mechanisms of synexpression (Grotewold et al, 2001), autoregulation (Beites et al, 2009), and feedback (Moustakas and Heldin, 2009). Thus, perturbation in the expression of one component often results in transcriptional misregulation of other components including secreted inhibitors.…”

Roles of innervation in developing and regenerating orofacial tissues

“…Sox2 is expressed in taste buds and the surrounding epithelial cells [18]. Molecules of the BMP and WNT signalling pathways regulate Sox2 expression in these tissues [30]. Taste bud epithelial cells differentiate into keratinocytes instead of sensory cells after Sox2 deletion [18].…”

“…Upregulation of BMP7 induces Sox2 expression that leads to the formation of ectopic taste buds and papillae in the tongue. Under these conditions, Sox2 expression is induced ectopically through a process that is independent of innervation [30].…”