Kir2.1 is important for efficient BMP signaling in mammalian face development

Abstract

Mutations that disrupt the inwardly rectifying potassium channel Kir2.1 lead to Andersen-Tawil syndrome that includes periodic paralysis, cardiac arrhythmia, cognitive deficits, craniofacial dysmorphologies and limb defects. The molecular mechanism that underlies the developmental consequences of inhibition of these channels has remained a mystery. We show that while loss of Kir2.1 function does not affect expression of several early facial patterning genes, the domain in which Pou3f3 is expressed in the maxillary arch is reduced. Pou3f3 is important for development of the jugal and squamosal bones. The reduced expression domain of Pou3f3 is consistent with the reduction in the size of the squamosal and jugal bones in Kcnj2 animals, however it does not account for the diverse craniofacial defects observed in Kcnj2 animals. We show that Kir2.1 function is required in the cranial neural crest for morphogenesis of several craniofacial structures including palate closure. We find that while the palatal shelves of Kir2.1-null embryos elevate properly, they are reduced in size due to decreased proliferation of the palatal mesenchyme. While we find no reduction in expression of BMP ligands, receptors, and associated Smads in this setting, loss of Kir2.1 reduces the efficacy of BMP signaling as shown by the reduction of phosphorylated Smad 1/5/8 and reduced expression of BMP targets Smad6 and Satb2.

L-type voltage-gated Ca2+channel CaV1.2 regulates chondrogenesis during limb development

“…As some ion channels are expressed with temporal and tissue specificity, endogenous spatiotemporal gradients of V mem can be generated across tissues and organs (1). Consistent with this, changes in V mem are known to influence embryonic development, among other processes (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

The Biophysics of Regenerative Repair Suggests New Perspectives on Biological Causation

“…Although channelopathies (including many human syndromes) reveal important endogenous roles of specific channel genes, this is just the tip of the iceberg. For example, the frog tadpole tail (Figure 3D–F) can regenerate using a 13‐subunit ion pump complex.…”

Ion Channels in Bone Morphogenetic Protein Signaling

“…32,33 Second, Kir2.1 and BMP signaling are both required in the cranial neural crest cells for the proliferation of the mesenchyme of the palatal shelves. 29,34,35 Third, E13.5 Kcnj2 KO/KO craniofacial tissues show a reduction in read-outs of BMP signaling such as phosphorylation of Smads1/5/8 and expression of BMP transcriptional targets. 29 However, TGF-b signaling seems to be intact in Kcnj2 KO/KO tissue.…”

“…For example, similar to mice in which BMP signaling components have been removed from the cranial neural crest, Kcnj2 KO/KO mice have hypoplastic maxilla, hypoplastic mandibles lacking the coronoid process, a cleft palate, and hypoplastic frontal bones leaving an enlarged fontanelle. [29][30][31] Loss of Kir2.1 leads to similar limb patterning defects as loss of BMP ligands from the limb buds. 32,33 Second, Kir2.1 and BMP signaling are both required in the cranial neural crest cells for the proliferation of the mesenchyme of the palatal shelves.…”