Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear

Abstract

Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (drJ/drJ), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a’s role as a selector gene. More importantly, while all three primary fates of the inner ear – neural, sensory, and non-sensory – are specified in drJ/drJ, normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.

A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

“…The APC gene is involved in various forms of cancer (hereditary and somatic) (Aoki and Taketo 2007), and when tested using Sanger sequencing, it did not segregate with the phenotype. The LMX1A gene was of interest as it had previously been implicated in a mouse autosomal recessive deafness phenotype (Koo et al 2009), and very recently, it has been described in human autosomal dominant hearing impairment (Wesdorp et al 2018). The missense variant in LMX1A [dbSNP:rs763320093; NM_001174069:c.1106T>C:p.Ile-369Thr], present in the 1q23.3-24.2 homozygous region, using Sanger sequencing, was found to segregate with HI (Fig.…”

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

“…Inefficient formation of constrictions between the different ear compartments and failure in the separation of the different sensory epithelia has also been observed in conditional N-Myc and Pax2 mutants as well as in Dreher (Lmx1a-/-) mice (Nichols et al, 2008;Koo et al, 2009;Bouchard et al, 2010;Kopecky et al, 2011) suggesting that the two processes are closely linked. The lack of constrictions might be due to failure in non-sensory specification since Lmx1a is expressed in non-sensory and not in the sensory epithelia.…”

“…The two crista stuctures that formed most likely corresponded to un-separated anterior and lateral cristae and a distinct posterior crista. A failure in the separation of the anterior and lateral cristae have also been observed in Dreher mice with mutation in Lmx1a gene and in the conditional Foxg1À/À mutant embryos (Nichols et al, 2008;Hwang et al, 2009;Koo et al, 2009) but their exact role in crista separation and their relation to Gata3 is currently unknown.…”

Molecular Mechanisms of Inner Ear Development

“…Fate-mapping results from both chicken and mouse suggest that vestibular neuroblasts are first to delaminate from the lateral region of the NSD, whereas auditory neuroblasts delaminate slightly later from the medial region Bell et al 2008). The two neurogenic regions within the otic epithelium where neuroblasts exit are also molecularly distinct from each other; the vestibular region is Fgf3-positive, whereas the auditory region is Gata3-and Lmx1a-positive (Lawoko- Kerali et al 2004;Koo et al 2009). Furthermore, in the absence of Lmx1a, the vestibular neurogenic marker Fgf3 is expanded medially, and there is an increase in the production of vestibular neurons as a result (Koo et al 2009).…”

“…The two neurogenic regions within the otic epithelium where neuroblasts exit are also molecularly distinct from each other; the vestibular region is Fgf3-positive, whereas the auditory region is Gata3-and Lmx1a-positive (Lawoko- Kerali et al 2004;Koo et al 2009). Furthermore, in the absence of Lmx1a, the vestibular neurogenic marker Fgf3 is expanded medially, and there is an increase in the production of vestibular neurons as a result (Koo et al 2009). Therefore, the vestibular and auditory neuroblasts may acquire their fates based on their position of origin within the developing ML axis of the inner ear.…”