Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

Abstract

DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development of neural crest cells (NCs) that colonize the pharyngeal arches and contribute to lower jaw, neck and heart tissues. Although TBX1 has been identified as the main gene accounting for the defects observed in human patients and mouse models, the molecular mechanisms underlying DGS etiology are poorly identified. The recent demonstrations that the SDF1/CXCR4 axis is implicated in NC chemotactic guidance and impaired in cortical interneurons of mouse DGS models prompted us to search for genetic interactions between Tbx1, Sdf1 (Cxcl12) and Cxcr4 in pharyngeal NCs and to investigate the effect of altering CXCR4 signaling on the ontogeny of their derivatives, which are affected in DGS. Here, we provide evidence that Cxcr4 and Sdf1 are genetically downstream of Tbx1 during pharyngeal NC development and that reduction of CXCR4 signaling causes misrouting of pharyngeal NCs in chick and dramatic morphological alterations in the mandibular skeleton, thymus and cranial sensory ganglia. Our results therefore support the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology.

Neural crest delamination and migration: Looking forward to the next 150 years

“…Another molecule that could guide chick cephalic NC cells is Sdf1. It is expressed in the ectoderm at the onset of migration and later in the branchial arches (Escot et al, 2013(Escot et al, , 2016. Interestingly, Sdf1 is also important for directional migration of cephalic NC in zebrafish (Olesnicky Killian et al, 2009).…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…The phenotypical presentation of human neurocristopathies commonly includes features that have been described in domesticated mammals [Sánchez-Villagra et al, 2016]. Interestingly, well-defined neurocristopathies like velocardiofacial syndrome (OMIM #192430) and DiGeorge syndrome (OMIM #188400) involve schizophrenic features [Mølsted et al, 2010;Zhang et al, 2014;Escot et al, 2016]. Likewise, given the NC derivation of most craniofacial structures, the craniofacial abnormalities observed in SZ are believed to result from disturbances in neuroectodermal development, hence representing putative external biomarkers of atypical brain growth [Compton et al, 2007;Aksoy-Poyraz et al, 2011] and suggesting an additional connection between SZ and domestication at the level of NC functional implications.…”

Choanal atresia and stenosis: Development and diseases of the nasal cavity

“…Hemizygous deletion of chromosome 22q11.2 in humans results in DiGeorge syndrome, which is another neurocristopathy associated with a broad range of craniofacial abnormalities, including CA (Epstein, 2001). Mutations in TBX1, which lies within the deletion region, has been shown to be a major contributor to the overall phenotype of DiGeorge syndrome ( (Escot et al, 2016). These results suggest that disruption of neural crest cell migration may underlie the pathogenesis of CA in DiGeorge syndrome.…”

“…Furthermore, Tbx1 plays a critical extrinsic role in neural crest cell development, especially migration, which is essential for proper craniofacial and cardiovascular development (Moraes, Nóvoa, Jerome‐Majewska, Papaioannou, & Mallo, ; Vitelli, Morishima, Taddei, Lindsay, & Baldini, ). TBX1 can activate Cxcr4 , which encodes a chemotactic guidance molecule for neural crest cells (Escot et al, ). These results suggest that disruption of neural crest cell migration may underlie the pathogenesis of CA in DiGeorge syndrome.…”