Autoregulation of Neurogenesis by GDF11

Abstract

In the olfactory epithelium (OE), generation of new neurons by neuronal progenitors is inhibited by a signal from neurons themselves. Here we provide evidence that this feedback inhibitory signal is growth and differentiation factor 11 (GDF11). Both GDF11 and its receptors are expressed by OE neurons and progenitors, and GDF11 inhibits OE neurogenesis in vitro by inducing p27(Kip1) and reversible cell cycle arrest in progenitors. Mice lacking functional GDF11 have more progenitors and neurons in the OE, whereas mice lacking follistatin, a GDF11 antagonist, show dramatically decreased neurogenesis. This negative autoregulatory action of GDF11 is strikingly like that of its homolog, GDF8/myostatin, in skeletal muscle, suggesting that similar strategies establish and maintain proper cell number during neural and muscular development.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…GDF-11 (also known as BMP-11), its receptors, and its antagonist follistatin, are expressed by progenitors and olfactory receptor neurons in the olfactory epithelium. GDF-11 is a negative growth regulator of olfactory receptor neurons and impairs proliferation of neuronal precursors, whereas follistatin reverses this effect (Wu et al 2003;Lander et al 2009;Gokoffski et al 2011). Thus, the TGF-b family regulates persistent neurogenesis in the adult olfactory system, stimulating production of olfactory receptor neurons when necessary.…”

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

“…5B). Secreted by myocytes, GDF8, also known as Myostatin, is an important negative regulator of skeletal muscle growth (Hill et al, 2002;Lee and McPherron, 2001;McPherron et al, 1997), whereas GDF11, secreted by mature neurons, serves a comparable function in inhibiting neurogenesis (Wu et al, 2003). GDF11 also appears to play roles in anterior-posterior patterning of the axial skeleton (McPherron et al, 1999).…”

Molecular Conservation and Novelties in Vertebrate Ear Development

“…Based on data in the CNS, the presence of either Ngn1 or NeuroD (alternate symbol for Neurod1) seems to be involved in the continued proliferation of neuroblasts through interference with the cell cycle (Bertrand et al, 2002). Indeed, factors involved in regulating proliferation are only now becoming apparent in other developing systems such as muscle and olfactory epithelium (Wu et al, 2003). How many of these regulatory elements are utilized in the ear remains speculative at the moment.…”

“…Interestingly, Ngn1 is also essential for olfactory sensory neuron formation (Wu et al, 2003). Assuming conservation of bHLH function, this suggests that the many sensory organs in the skin of the lancelet may be directed in their development by an as yet undetected proneuronal bHLH gene(s).…”