Intracellular attenuation of BMP signaling via CKIP-1/Smurf1 is essential during neural crest induction

Abstract

The neural crest is induced at the neural plate border during gastrulation by combined bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling. While intermediate BMP levels are critical for this induction, secreted BMP inhibitors are largely absent from the neural plate border. Here, we propose a morphogen model in which intracellular attenuation of BMP signaling sets the required intermediate levels to maintain neural crest induction. We show that the scaffold protein casein kinase interacting protein 1 (CKIP-1) and ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) are coexpressed with BMP4 at the chick neural plate border. Knockdown of CKIP-1 during a critical period between gastrulation and neurulation causes neural crest loss. Consistent with specific BMP modulation, CKIP-1 loss suppresses phospho-Smads 1/5/8 (pSmad1/5/8) and BMP reporter output but has no effect on Wnt signaling; Smurf1 overexpression (OE) acts similarly. Epistasis experiments further show that CKIP-1 rescues Smurf1-mediated neural crest loss. The results support a model in which CKIP-1 suppresses Smurf1-mediated degradation of Smads, uncovering an intracellular mechanism for attenuation of BMP signaling to the intermediate levels required for maintenance of neural crest induction.

Specification and formation of the neural crest: Perspectives on lineage segregation

“…Toward this end, the nuclear coactivator SNW1 was found to act upstream of BMP signaling and to regulate its effect in the restricted domain of the neural plate border in postgastrula Xenopus embryos (Wu, Ramel, Howell, & Hill, 2011). Further, a recent study in chick suggests the role of CKIP-1/Smurf1 in modulating the precise level of phospho-Smad1/5/8 at the neural plate border required to maintain neural crest induction (Piacentino & Bronner, 2018).…”

A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm

“…FGF agonists, together with an attenuation of BMP and WNT signaling, initiate placodal emergence indicated by expression of SIX1 and EYA1/2 (Ahrens and Schlosser, 2005;Bhat et al, 2013;Kwon et al, 2010;Litsiou et al, 2005). Similarly, neural crest differentiation requires FGF signaling together with an intermediate BMP signaling level (Geary and LaBonne, 2018;Piacentino and Bronner, 2018;Stuhlmiller and García-Castro, 2012;Villanueva et al, 2002;Yardley and García-Castro, 2012). Unlike placodes, the specification of neural crest (marked by PAX3/7 and SOX9/10) at the neural plate border is dependent on a source of secreted WNT ligands from the paraxial mesoderm or the ectoderm itself (García-Castro et al, 2002;Litsiou et al, 2005;Sato et al, 2005;.…”

Bimodal function of chromatin remodeler Hmga1 in neural crest induction and Wnt-dependent emigration

“…Neural crest induction, specification, and emigration from the neural tube are intricate processes that require an interplay between Wnt, FGF, and BMP signaling pathways ( Piacentino and Bronner, 2018 ; Woda et al, 2003 ) working reiteratively at different stages of development. For example, at the onset of neural crest emigration, Wnt1 is prominently expressed in the dorsal neural tube, where premigratory neural crest cells reside ( Simões-Costa et al, 2015 ).…”