PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation

Abstract

Despite being implicated as a mechanism driving gastrulation and body axis elongation in mouse embryos, the cellular mechanisms underlying mammalian convergent extension (CE) are unknown. Here we show, with high-resolution time-lapse imaging of living mouse embryos, that mesodermal CE occurs by mediolateral cell intercalation, driven by mediolaterally polarized cell behavior. The initial events in the onset of CE are mediolateral elongation, alignment and orientation of mesoderm cells as they exit the primitive streak. This cell shape change occurs prior to, and is required for, the subsequent onset of mediolaterally polarized protrusive activity. In embryos mutant for PTK7, a novel cell polarity protein, the normal cell elongation and alignment upon leaving the primitive streak, the subsequent polarized protrusive activity, and CE and axial elongation all failed. The mesoderm normally thickens and extends, but on failure of convergence movements in Ptk7 mutants, the mesoderm underwent radial intercalation and excessive thinning, which suggests that a cryptic radial cell intercalation behavior resists excessive convergence-driven mesodermal thickening in normal embryos. When unimpeded by convergence forces in Ptk7 mutants, this unopposed radial intercalation resulted in excessive thinning of the mesoderm. These results show for the first time the polarized cell behaviors underlying CE in the mouse, demonstrate unique aspects of these behaviors compared with those of other vertebrates, and clearly define specific roles for planar polarity and for the novel planar cell polarity gene, Ptk7, as essential regulators of mediolateral cell intercalation during mammalian CE.

Potential Relation of Aberrant Proteolysis of Human Protein Tyrosine Kinase 7 (PTK7) chuzhoi by Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) to Congenital Defects

“…Because PTK7 readily oligomerizes through its ectodomain (10,52), membrane PTK7 forms a complex either with itself or with the solubilized ectodomain or with some yet to be identified adaptor protein(s) (2, 13, 39 -41, 43, 48). It is likely that these different complex types elicit the dissimilar downstream signaling events and that these signaling events differentially regulate multiple cell functions, including PCP and directional motility, in processes as diverse as cancer cell invasion and embryonic cell migration during gastrulation in eukaryotes (13,18,28,30). In agreement, the soluble PTK7 ectodomain inhibited angiogenesis in vitro and in vivo in a dominant-negative fashion by competing with full-length PTK7 (12).…”

“…Ubiquitously expressed PTK7 (also called colon carcinoma kinase-4 (CCK-4)) is a Wnt coreceptor and a regulator of PCP in vertebrates (7)(8)(9)(10)(11)(12)(13). Membrane PTK7 includes seven extracellular Ig domains, a transmembrane region, and a catalytically inert cytoplasmic tyrosine kinase (PTK) domain (8,9,11,14).…”

Identification of emergent motion compartments in the amniote embryo

“…Remarkably, experimental observations from the mouse gastrula suggest that the forces generated by radial intercalation (reminiscent of the forces in our lateral epiblastic explants) tend to oppose the tendency for convergence forces to elongate the midline tissue (reminiscent of the forces in our nodal tissue explants). 46 Ultimately, it is possible that the lateral width of the avian gastrula is set by striking a balance between local cell-cell cohesion forces in the lateral epiblast and global tensional forces across the entire epithelium.…”

PTK7 is a molecular marker for metastasis, TNM stage, and prognosis in oral tongue squamous cell carcinoma

“…PTK7 is an evolutionarily conserved transmembrane protein containing seven immunoglobulin domains, a transmembrane domain, and a catalytically inactive kinase domain [6,7,8].PTK7isaWntco-receptorandanimportantregulatorofplanarcellpolarity(PCP)anddirectionalcellmotilityinembryogenesisandvertebrate development [9,10,11]. The PCP signaling pathways control cell mobility and cellular polarity, re-sultinginmodificationofthecytoskeleton.DeregulationofPCPcancausevariouspathologicdisorders, including cancer.…”