Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid

Abstract

Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APC Cdh1 E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/ Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc.

Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models

“…In mouse models, Cdh1 knockout is embryonic lethal and mutant embryos do not develop beyond E10.5 (Garcia-Higuera et al, 2008). Conditional Cdh1 knockout in neural crest cells results in craniofacial defects related to bone development, including a shortened snout, abnormal teeth and twisted nasal bones (Shao et al, 2016). However, these mutants did not develop orofacial clefts.…”

GATA4 as a novel regulator involved in the development of the neural crest and craniofacial skeleton via Barx1

“…For the luciferase reporter experiments [ 44 ], 293T cells were cultured in 24-well plates at a density of 1.0 × 10 5 cells per well. When cells grew to 80%, they were co-transfected with pEZ-GATA4, pEZ- Barx1 promoter-luciferase (100 ng per well), and plasmid pEZ-SV40 (10 ng per well) using Polyetherimide.…”

Quiescence Entry, Maintenance, and Exit in Adult Stem Cells

“…In adult neural stem cells, the ubiquitin E3 ligase APC/C (anaphase-promoting complex) controls a balance between the cell quiescence maintenance program and the programs for cell quiescence exit, proliferation, and differentiation, because it primes for proteasome degradation or non-proteolytically activates certain cell-cycle regulation proteins, transcription factors, translation factors, and cell surface receptor proteins [284,354,355,356,357,358,359]. HUWE1 (HECT, UBA and WWE domain containing protein 1), another ubiquitin E3 ligase in adult neural stem cells, stimulates a re-entry of early neural progenitor cells into the quiescent state, because it ubiquitinates and primes some transcription factors for proteasome degradation, cell-cycle regulation proteins, and apoptotic death regulators [284,360,361,362,363,364].…”