Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice

Abstract

Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and VCSF using mouse models. The hallmark of Tbx1 haploinsufficiency is hypo/aplasia of the fourth pharyngeal arch artery (PAA) at E10.5. Identical malformations were observed in Chd7 heterozygotes, with resulting aortic arch interruption at later stages. Other than Tbx1, Chd7 is the only gene reported to affect fourth PAA development by haploinsufficiency. Moreover, Tbx1 +/-;Chd7 +/-double heterozygotes demonstrated a synergistic interaction during fourth PAA, thymus, and ear morphogenesis. We could not rescue PAA morphogenesis by restoring neural crest Chd7 expression. Rather, biallelic expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…Mouse models have provided compelling evidence in support of this hypothesis, linking CHD7 to many important developmental pathways. For instance, Fgf8 interacts with Chd7 during early cerebellar vermis development (Yu et al, 2013), and Chd7 interacts with Tbx1 during arch vessel development (Randall et al, 2009). As cerebellar foliation is under genetic control (see section 1), it seems likely that genes controlling this process may be regulated by CHD7 and interact with Chd7 .…”

“…The Chd7 xk403/+ gene trap ( Chd7 gt/+ ) mouse line has been described (Randall et al, 2009) and was maintained on a B6D2F1 background. Genotyping was performed from ear or tail DNA.…”

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

“…Therefore, Gbx2 is a shared target, and the rescue of its expression in double mutants could explain phenotypic rescue. Gbx2 and Tbx1 are coexpressed in the pharyngeal surface ectoderm and in the pharyngeal endoderm (17), tissues that have been linked to the fourth PAA phenotype (17,27,28). In addition, Gbx2 is required for PAA and OFT development (16).…”

CHARGE syndrome: a review of the immunological aspects

“…The 22q11.2 region contains the TBX1 gene (#MIM 602054), which has been identified as a candidate gene for most of the phenotypic features seen in the 22q11.2 deletion syndrome. 40 The existence of a shared embryonic pathway or pathways of CHD7 and TBX1 has been studied for heart development 56 and inner ear development 57 in animal models. Both genes are expressed in the pharyngeal arches, of which the third and fourth arches contain the precursors of the thymic stromal cells.…”

“…68 A common pathway for CHD7 and fibroblast growth factor 8 (FGF8)/FGFR1 has therefore been suggested. 56,69,70 FGFR1 is expressed in a subset of T-cells and is believed to interact with the T-cell receptor to enhance the activation of T-cells. 71 Table 2 Phenotypic comparison of our collected cohort with a proven variant in CHD7 compared with cohorts with a proven variant in CHD7 from the literature Kabuki syndrome is caused by variants in KMT2D (#MIM 602113), affecting the function of a methyltransferase named MLL2 that is involved in transcriptional regulation.…”