BMP type I receptor complexes have distinct activities mediating cell fate and axon guidance decisions

Abstract

The finding that morphogens, signalling molecules that specify cell identity, also act as axon guidance molecules has raised the possibility that the mechanisms that establish neural cell fate are also used to assemble neuronal circuits. It remains unresolved, however, how cells differentially transduce the cell fate specification and guidance activities of morphogens. To address this question, we have examined the mechanism by which the Bone morphogenetic proteins (BMPs) guide commissural axons in the developing spinal cord. In contrast to studies that have suggested that morphogens direct axon guidance decisions using noncanonical signal transduction factors, our results indicate that canonical components of the BMP signalling pathway, the type I BMP receptors (BMPRs), are both necessary and sufficient to specify the fate of commissural neurons and guide their axonal projections. However, whereas the induction of cell fate is a shared property of both type I BMPRs, axon guidance is chiefly mediated by only one of the type I BMPRs, BMPRIB. Taken together, these results indicate that the diverse activities of BMP morphogens can be accounted for by the differential use of distinct components of the canonical BMPR complex.

Type Ib BMP receptors mediate the rate of commissural axon extension through inhibition of cofilin activity

“…The specification of commissural cell fate is a redundant function of both type I Bmprs, BmprIa and BmprIb (Timmer et al, 2002;WineLee et al, 2004). By contrast, only BmprIb is required in commissural neurons to reorient their axons away from the RP (Yamauchi et al, 2008). Here, we show that BmprIb, but not BmprIa, is also required for the ability of BMPs to control the rate of commissural axon outgrowth, lending further support to a model in which BmprIb uniquely functions to mediate the ability of BMPs to act as axon guidance signals.…”

“…However, the mechanism by which a commissural neuron discriminates between the canonical Smad and non-canonical Limk1-cofilin signaling pathway remains unclear. Our studies have suggested that this choice depends on which type I Bmprs are present in the cell during development (Yamauchi et al, 2008). The specification of commissural cell fate is a redundant function of both type I Bmprs, BmprIa and BmprIb (Timmer et al, 2002;WineLee et al, 2004).…”

“…Hamilton and Hamburger (HH) stage 13-15 (Hamburger and Hamilton, 1992) White Leghorn chick embryos (AA Laboratory Eggs) were electroporated and processed as previously described (Yamauchi et al, 2008). Math1 (Atoh1) enhancer expression constructs were generated as previously described (Phan et al, 2010).…”

“…For HH stages 22/23 and 27/28, axon outgrowth was quantified as previously described (Fig. 1L) (Yamauchi et al, 2008). At HH stage 27/28, the Lhx2/9 + cell bodies have started their migration into deeper layers of the dorsal spinal cord, thus there are more axons at the intermediate (INT) level compared with the mid-dorsal (MD) boundary.…”

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

“…In support of this suggestion, the present study has demonstrated that both BMP2 and GDF5 promote neurite outgrowth from E14 VM neurons in culture. BMP2 and GDF5 may also act to orientate the axons of VM DA neurons away from the VM, since other BMPs, such as BMP7 and GDF7, have been shown to orient the commissural axons of dorsal SC interneurons via BMPRIb (Butler and Dodd 2003;Dent et al 2011;Phan et al 2010;Yamauchi et al 2008;Wen et al 2007). The sustained expression of BMPRs in the VM during adulthood suggests that they may function in the maintenance of DA neurons, with both BMP2 and GDF5 being shown to promote the survival of VM DA neurons in vitro (O'Keeffe et al 2004a;Wood et al 2005;Reiriz et al 1999;Jordan et al 1997) and in vivo (Sullivan et al 1997(Sullivan et al , 1998(Sullivan et al , 1999Hurley et al 2004;O'Sullivan et al 2010;Espejo et al 1999).…”