BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

Abstract

Induction of the sympathetic nervous system (SNS) from its neural crest (NC) precursors is dependent on BMP signaling from the dorsal aorta. To determine the roles of BMP signaling and the pathways involved in SNS development, we conditionally knocked out components of the BMP pathways. To determine if BMP signaling is a cell-autonomous requirement of SNS development, the Alk3 (BMP receptor IA) was deleted in the NC lineage. The loss of Alk3 does not prevent NC cell migration, but the cells die immediately after reaching the dorsal aorta. The paired homeodomain factor Phox2b, known to be essential for survival of SNS precursors, is downregulated, suggesting that Phox2b is a target of BMP signaling. To determine if Alk3 signals through the canonical BMP pathway, Smad4 was deleted in the NC lineage. Loss of Smad4 does not affect neurogenesis and ganglia formation; however, proliferation and noradrenergic differentiation are reduced. Analysis of transcription factors regulating SNS development shows that the basic helix-loop-helix factor Ascl1 is downregulated by loss of Smad4 and that Ascl1 regulates SNS proliferation but not noradrenergic differentiation. To determine if the BMP-activated Tak1 (Map3k7) pathway plays a role in SNS development, Tak1 was deleted in the NC lineage. We show that Tak1 is not involved in SNS development. Taken together, our results suggest multiple roles for BMP signaling during SNS development. The Smad4-independent pathway acts through the activation of Phox2b to regulate survival of SNS precursors, whereas the Smad4-dependent pathway controls noradrenergic differentiation and regulates proliferation by maintaining Ascl1 expression.

Sequential requirement of Sox4 and Sox11 during development of the sympathetic nervous system

“…Most other transcription factors that have been identified as regulators in the sympathoadrenal lineage primarily exert their effect on differentiation rather than proliferation. Early proliferative defects, similar to those found in Sox11-deficient as well as in Sox4 and Sox11 double-deficient SG, have been observed in mice deficient for Insm1 (Wildner et al, 2008), Hand2 (Hendershot et al, 2008;Schmidt et al, 2009) and Mash1 (Morikawa et al, 2009). In Sox4/Sox11-deficient and Insm1-deficient mice, proliferation rates were reduced until 12.5 dpc but had normalized or even increased above controls by 14.5 dpc.…”

Establishing neural crest identity: a gene regulatory recipe

“…For instance, neuregulin signaling biases neural crest progenitors to adopt a peripheral glial fate, whereas BMPs promote neuronal differentiation (Stemple and Anderson, 1993). Sympathetic neurons are specified by BMP signaling secreted by the dorsal aorta (Saito et al, 2012), which cooperates with Sox10 to activate expression of the sympathetic neuron specifier genes Phox2b and Ascl1 (Morikawa et al, 2009) (Fig. 7D and Fig.…”

Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition

“…Proliferation of precursors and immature sympathetic neurons are affected by the transcription factors Ascl1, Phox2b, Hand2, Insm1, Sox11 and Gata2/3 that were previously considered to control only initial specification and differentiation (Coppola et al, 2010;Hendershot et al, 2008;Morikawa et al, 2009;Pattyn et al, 1999;Potzner et al, 2010;Tsarovina et al, 2010;Wildner et al, 2008). Mutations in the PHOX2B gene were identified in familial cases of NB and result in tumor predisposition (McConville et al, 2006;Mosse et al, 2004;Trochet et al, 2004;van Limpt et al, 2004).…”