Target-dependent inhibition of sympathetic neuron growth via modulation of a BMP signaling pathway

Abstract

Target-derived factors modulate many aspects of peripheral neuron development including neuronal growth, survival, and maturation. Less is known about how initial target contact regulates changes in gene expression associated with these developmental processes. One early consequence of contact between growing sympathetic neurons and their cardiac myocyte targets is the inhibition of neuronal outgrowth. Analysis of neuronal gene expression following this contact revealed coordinate regulation of a bone morphogenetic protein (BMP)-dependent growth pathway in which basic helix-loop-helix transcription factors and downstream neurofilament expression contribute to the growth dynamics of developing sympathetic neurons. BMP2 had dose-dependent growth-promoting effects on sympathetic neurons cultured in the absence, but not the presence, of myocyte targets, suggesting that target contact alters neuronal responses to BMP signaling. Target contact also induced the expression of matrix Gla protein (MGP), a regulator of BMP function in the vascular system. Increased MGP expression inhibited BMP-dependent neuronal growth and MGP expression increased in sympathetic neurons during the period of target contact in vivo. These experiments establish MGP as a novel regulator of BMP function in the nervous system, and define developmental transitions in BMP responses during sympathetic development.

Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin-4

“…The cell size of neurons has been suggested to positively correlate with the neuronal connections and the target area size [61,62]. The average size of PV-positive neurons in the neocortex of middle-aged Wistar rats was increased by approximately 20% (not statistically significant trend) in comparison with young Wistars, an effect that was not observed in T2D GK rats (Figure 6A).…”

The Regulation of Cell Size

“…Postmitotic neurons often extend very long axons to innervate their target tissue, a growth process stimulated by local neurotrophins and other signaling molecules that control the guidance of the axon (Bellon et al, 2010;Chilton, 2006). Upon target innervation, signals from the target tissue inhibit further axonal extension (Moon and Birren, 2008), but then the level of growth factors expressed by the target tissue determines and maintains the size of the neuron (Fawcett and Keynes, 1990;Purves et al, 1988). This has been particularly well established for sympathetic neurons for which the level of NGF in the target tissue sets the size of the cell.…”

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

“…Additional signals from cardiac tissue regulate developmental transitions between different growth states in sympathetic neurons. For example, contact with cardiac tissue results in a change in the neuronal response to bone morphogenetic proteins (BMPs), providing a stop-growth signal for sympathetic axons that have reached their target (Moon & Birren, 2008). Interacting actions of neurotrophic factors (Habecker et al 2008;Lorentz et al 2010) and Sema3a signalling are also likely to act in the patterning of sympathetic fibres within the heart.…”