Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Abstract

The T-box transcription factor TBX1 has been identified as the major gene responsible for the etiology of velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutations in POU3F4/BRN4, a POU domain transcription factor, cause DFN3, an X-linked nonsyndromic form of deafness characterized by mixed conductive and sensorineural hearing loss. Inactivation of the murine orthologues of these genes causes similar defects to those seen in humans and has provided excellent models for the study of inner ear development. Tbx1 and Brn4 are expressed in the mesenchymal cells surrounding the otic vesicle and have been shown to play roles in cochlear outgrowth. Furthermore, expression of Brn4 is reduced in Tbx1 null mutants, suggesting a possible genetic interaction between these genes. To test whether Tbx1 and Brn4 function in a common pathway, mice mutant for both genes were generated and analyzed for inner ear defects. Brn4−;Tbx1+/− mutants displayed a significant reduction in the number of turns of the cochlea compared to Brn4− or Tbx1+/− mice. In addition, Brn4−;Tbx1+/− mice displayed structural defects in the apical cochlea indicative of Mondini dysplasia found in patients with either VCFS/DGS or DFN3. These data establish a genetic interaction between Tbx1 and Brn4 relevant to human disease and indicate a function of these genes in signaling from the periotic mesenchyme to the otic vesicle to direct proper coiling of the cochlear duct.

MicroRNA-182 regulates otocyst-derived cell differentiation and targets T-box1 gene

“…Homozygous mutation of the mouse homolog Tbx1 is associated with severe inner ear defects that prevent the development of the cochlea and vestibule (Raft et al, 2004;Vitelli et al, 2003). Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme (Braunstein et al, 2008). Tbx1 loss-of-function blocks inner ear development at the early otocyst stage and after neurogenesis.…”

Defects in sensory organ morphogenesis and generation of cochlear hair cells in Gata3-deficient mouse embryos

“…GATA3 is likely to regulate the differentiation of the auditory sensory epithelium cell autonomously and in fact, down-regulation of Gata3 in cultured immortalized auditory sensory epithelial cells leads to the loss of Cdkn1b expression (Milo et al, 2009). However, since Gata3 is expressed in the cochlear mesenchyme (Lilleväli et al, 2004), it may also be involved in the control of signaling events from the mesenchyme that participate in cochlear morphogenesis and cell differentiation (Montcouquiol and Kelley, 2003;Doetzlhofer et al, 2004;Xu et al, 2007;Braunstein et al, 2008).…”

Association of congenital microtia with environmental risk factors in South Korea

“…Both hereditary and environmental factors contribute to the occurrence of microtia; however, the factors with the most pronounced effects remain unknown. Chromosomal abnormalities can lead to the occurrence of microtia, including trisomies of chromosomes 13, 18, and 21 [6] and mutations in specific genes, such as TCOF1 [7], HOXA2 [8], HOXA1 [9], TBX1 [10], and BAPX1 [11]. Several environmental factors are also considered risk factors for microtia, including prenatal exposure to drugs [3], high parity [3,12], paternal age [13], first parity [3], maternal diabetes [3], year of delivery [12], population origin [4,12], high maternal age [4], altitude [14], urban area [15], and less years of maternal education [4].…”