The Role of Hoxa3 Gene in Parathyroid Gland Organogenesis of the Mouse

Abstract

S U M M A R YMice with a targeted deletion of the Hoxa3 gene have defects of derivatives of the third branchial arch and pouch. To address the role of the Hoxa3 gene in parathyroid organogenesis, we examined the third pharyngeal pouch development by immunohistochemistry (IHC) using the secretory protein (SP)-1/chromogranin A antiserum, which recognizes the parathyroid from its initial formation onward. At embryonic day (E) 11.5, the SP-1/chromogranin A-immunoreactive primary rudiment of the parathyroid appeared in the cranial region of the third pharyngeal pouch of wild-type embryos. In Hoxa3 -null mutants, the third pharyngeal pouch was normally formed but failed to differentiate into the parathyroid rudiment, showing no immmunoreactivity for SP-1/chromogranin A. Classic studies using chick-quail chimeras have demonstrated that the ectomesenchymal neural crest cells are required for proper development of the pharyngeal pouch-derived organs, including the thymus and parathyroid glands. To visualize the migration and development of mesenchymal neural crest cells in Hoxa3 mutants, the heterozygotes were crossed with connexin43-lacZ transgenic mice in which ␤ -galactosidase expression was specific to the neural crest cells. In Hoxa3 homozygotes and in wild types, ectomesenchymal neural crest cells densely populated the pharyngeal arches, including the third one, and surrounded the third pouch epithelium. These results indicate that lack of the Hoxa3 gene affects the intrinsic ability of the third pharyngeal pouch to form the parathyroid rudiment and has no detectable effect on the migration of neural crest cells.

Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse

“…3H,I). These results are consistent with previous reports that show the absence of other parathyroid differentiation markers at E11.5 (Kameda et al, 2004) and the loss of prospective parathyroid cells through apoptosis at E12.5 in Gcm2 −/− mutants (Liu et al, 2007). ΔNp63 is reported to mark thymic epithelial precursor cells (Senoo et al, 2007), although its expression before E12.0 in the third pharyngeal pouch has not been described.…”

“…Hoxa3 was the first Hox gene to be mutated in mice by homologous recombination, and the null phenotype has been well characterized (Chisaka and Capecchi, 1991;Capecchi, 1995, 1998;Su et al, 2001;Kameda et al, 2002Kameda et al, , 2003Kameda et al, , 2004Gaufo et al, 2003). Hoxa3 has an anterior expression limit at the third pharyngeal arch and is expressed in all cell populations in the pharyngeal region, including endoderm, ectoderm, mesoderm and neural crest cells (NCCs) (Gaunt, 1987(Gaunt, , 1988Chisaka and Capecchi, 1991;Manley and Capecchi, 1995).…”

“…At E11.0, Foxn1 (Forkhead box N1) expression marks the thymus domain and is necessary for thymic epithelial cell (TEC) proliferation and differentiation (Nehls et al, 1994(Nehls et al, , 1996Manley and Condie, 2010). Previously, we have shown that in the Hoxa3 null mouse, Gcm2 is reduced at E10.5 and Foxn1 is lacking at E11.5 (Chen et al, 2010); other parathyroid differentiation markers are also undetectable at E12.0 (Kameda et al, 2004). As Hox genes are classically considered to specify positional identity, these molecular data together with the perinatal phenotype suggest that HOXA3 acts to specify third pharyngeal pouch identity and that, in its absence, organ specification fails .…”

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

“…The variability in phenotypic expression of heterozygous mutation may be conditioned by polygenic mechanism or by environmental factors (57,58). Among the polygenic factors, possibilities include mutations in the parathyroid glandrelated transcription factor proteins other than GCM2 such as PAX1, PAX9, GATA3, Hoxa3, TBX1, and SOX3 (6,9,(59)(60)(61)(62).…”

Parathyroid Development and the Role of Tubulin Chaperone E

“…This member of the Hox gene family, which specifies positional identity in the developing embryo [15], is strongly expressed in the 3rd pharyngeal arch and pouch from which the two parathyroid glands of mice develop, and in the 4th pharyngeal pouch endoderm and neural crest mesenchyme [22]. Inactivation of the Hoxa3 gene in mice results in parathyroid and thymic aplasia and persistent ultimobranchial bodies [22,23,24]. …”