The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice

Abstract

Neural tube defects (NTDs) are among common and severe birth defects with poorly understood etiology. Mutations in the Wnt coreceptor LRP6 are associated with NTDs in humans. Either gain-of-function (GOF) or loss-of-function (LOF) mutations of Lrp6 can cause NTDs in mice. NTDs in Lrp6-GOF mutants may be attributed to altered ß-catenin-independent noncanonical Wnt signaling. However, the mechanisms of NTDs in Lrp6-LOF mutants and the role of Lrp6-mediated canonical Wnt/ß-catenin signaling in neural tube closure remain unresolved. We previously demonstrated that ß-catenin signaling is required for posterior neuropore (PNP) closure. The current study shows that conditional ablation of Lrp6 in dorsal PNP causes spinal NTDs with diminished activities of Wnt/ß-catenin signaling and its downstream target gene Pax3 that is required for PNP closure. ß-catenin-GOF can rescue NTDs in Lrp6-LOF mutants. Moreover, maternal supplementation of a Wnt/ß-catenin signaling agonist can reduce the frequency and severity of spinal NTDs in Lrp6-LOF mutants by restoring Pax3 expression. Together, these results demonstrate the essential role of Lrp6-mediated Wnt/ß-catenin signaling in PNP closure, which may also provide a therapeutic target for NTD intervention through manipulation of canonical Wnt/ß-catenin signaling activities.

Balancing WNT signalling in early forebrain development: The role of LRP4 as a modulator of LRP6 function

“…Loss of LRP6 leads to neural tube defects (NTD) as reported before (Gray et al, 2010;Allache et al, 2014;Zhao et al, 2022), while no such defects have been observed in LRP4 loss-offunction mutants or Lrp5 −/− mutant embryos. Since Lrp4 and Lrp5 are highly expressed during forebrain development, they may have functional redundancy during early forebrain development.…”

“…Another prominent phenotype in mice carrying either gain-offunction or loss-of-function mutations of Lrp6 is neural tube defects (NTDs) with full penetrance of spina bifida and incomplete penetrance of anterior neural tube closure defects causing exencephaly (Pinson et al, 2000;Carter et al, 2005;Bryja et al, 2009;Gray et al, 2010;Gray et al, 2013;Zhou et al, 2010;Zhao et al, 2022). Multiple studies have reported patients with NTDs carrying mutations in the LRP6 gene (Allache et al, 2014;Lei et al, 2015;Shi et al, 2018).…”

“…Our data demonstrate the crucial roles of LRP4 and LRP6 in regulating WNT signalling and forebrain development and highlight the need to consider the interaction between different signalling pathways to understand the underlying mechanisms of disease. The findings have significant severe developmental disorders including neural tube defects (NTDs) (Copp et al, 2003;Wallingford, 2006;Ybot-Gonzalez et al, 2007;Wang et al, 2019;Brown et al, 2020;Zhao et al, 2022). Given that NTDs have a global prevalence of around 19 cases per 10,000 births and are therefore among the most common birth defects (Copp et al, 2003;Harris and Juriloff, 2007;Greene and Copp, 2014;Kakebeen and Niswander, 2021), it is crucial to understand the underlying pathomechanisms.…”

“…The severe developmental defects, caused by LRP6 deficiency, are associated with impaired canonical and non-canonical WNT signalling levels (Gray et al, 2010;Allache et al, 2014;Zhao et al, 2022). Decreased non-canonical WNT/PCP signalling may contribute to NTDs in hypermorphic Lrp6 mutants (Bryja et al, 2009;Gray et al, 2013;Allache et al, 2014), while another recent study demonstrated the essential role of LRP6-mediated canonical WNT/β-catenin signalling in the closure of the posterior neural tube (Zhao et al, 2022). These seemingly contradictory results suggest that cranial and spinal NTDs in LRP6-deficient mutants are caused by distinct pathomechanisms.…”

Wnt/planar cell polarity signaling controls morphogenetic movements of gastrulation and neural tube closure

“…Although LRP6 generally functions as a co-receptor in Wnt/ß-catenin signaling, there is evidence that it regulates neural tube closure through the Wnt/PCP pathway. In mice, both gain and loss of LRP6 activity affect neural tube closure and cause varying degrees of NTDs, which may be attributed to defective Wnt/ß-catenin or Wnt/PCP signaling [163,164,165,166,167,168].…”