Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene

Chizhikov, Victor V.; Steshina, Ekaterina Y.; Roberts, Richard W.; Ilkin, Yesim; Washburn, Linda L.; Millen, Kathleen J.

doi:10.1007/s00335-006-0033-7

Cited by 35 publications

(42 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homozygous Lmx1a mouse mutants (Dreher) have neurological, skeletal, and otic abnormalities (Chizhikov et al 2006), and exhibit circling behavior, balance abnormalities, and deafness. Heterozygotes littermates display normal hearing (Koo et al 2009; Steffes et al 2012).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmxla is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmxla mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Both the Lmx1a dr and Lmx1b flox alleles generate truncated proteins that are still recognized by the Lmx1a and Lmx1b specific antibodies. However, both alleles are very likely null alleles based on the similar brain phenotypes of homozygous Lmx1a dr/dr (Chizhikov et al, 2006b) and Wnt1cre/ϩ;Lmx1b flox/flox (Guo et al, 2007) (Fig. 3A-K ).…”

Section: Functional Cooperation Between Lmx1a and Lmx1b In Mda Neuronmentioning

confidence: 99%

Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors

Yan¹,

Lévesque²,

Claxton³

et al. 2011

J. Neurosci.

129

143

View full text Add to dashboard Cite

LIM homeodomain transcription factors, Lmx1a and Lmx1b, are required for the development of midbrain dopaminergic (mDA) neurons. Lmx1b is required for the specification and maintenance of mDA neurons, primarily due to its role in isthmic organizer development that is essential for the induction of mDA neurons. Here, we conditionally deleted Lmx1b in the ventral neural tube using ShhCre and found that Lmx1b conditional mutant mouse embryos show no defect in the development and maintenance of mDA neurons. In addition, Dreher (Lmx1a mutant) embryos display only a moderate reduction in the number of mDA neurons, suggesting that the related family member Lmx1b might compensate for Lmx1a function. We therefore generated Lmx1a and Lmx1b double mutants. Severe loss of mDA neurons occurred in Lmx1a dr/dr ;Shh Cre/ϩ ;Lmx1b f/f double mutants due to essential roles for Lmx1a and Lmx1b in regulating the proliferation and neuronal commitment of mDA progenitors through the expression of Wnt1 and Ngn2, respectively. Lmx1a and Lmx1b also negatively regulate Hes1 expression and consequently cell cycle exit through activation of p27 Kip1 expression. In addition, Lmx1a and Lmx1b also regulate the expression of floor plate genes such as Corin and Slit2 and specification of postmitotic mDA neurons. These defects were more severe with decreasing gene dosage of Lmx1a and Lmx1b or observed only when all four copies of Lmx1a and Lmx1b genes were inactivated. Together, our results demonstrate that Lmx1a and Lmx1b function cooperatively to regulate proliferation, specification, and differentiation of mDA progenitors, including their floor plate-like properties.

show abstract

“…The mutation results in abnormal formation of the roof plate and adjacent cerebellar rhombic lip, two structures that express Lmx1a during embryonic development. As a result, cerebellar development is significantly compromised (Millonig et al 2000; Chizhikov et al 2006; Chizhikov et al 2010). …”

Section: Introductionmentioning

confidence: 99%

“…Its expression expands into the adjacent rhombic lip by E12.5 (Chizhikov et al 2006; Chizhikov et al 2010). The roof plate is a transient signaling center that controls proliferation of the adjacent neuroepithelium and induces the rhombic lip.…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of Lmx1a function, these progenitors leave the rhombic lip prematurely and migrate into ectopic locations in the anterior vermis (Chizhikov et al 2010). Cumulatively, these defects result in gross cerebellar hypoplasia and abnormalities that are concentrated medially, with the most obvious being the absence of a normal cerebellar vermis (Sekiguchi et al 1992; Millonig et al 2000; Chizhikov et al 2006; Chizhikov et al 2010). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Purkinje cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher

et al. 2012

Self Cite

View full text Add to dashboard Cite

The cerebellar morphological phenotype of the spontaneous neurological mutant mouse dreher (Lmx1adr-J) results from cell fate changes in dorsal midline patterning involving the roof plate and rhombic lip. Positional cloning revealed that the gene Lmx1a, which encodes a LIM homeodomain protein, is mutated in dreher, and is expressed in the developing roof plate and rhombic lip. Loss of Lmx1a causes reduction of the roof plate, an important embryonic signaling center, and abnormal cell fate specification within the embryonic cerebellar rhombic lip. In adult animals, these defects result in variable, medial fusion of the cerebellar vermis and posterior cerebellar vermis hypoplasia. It is unknown whether deleting Lmx1a results in displacement or loss of specific lobules in the vermis. To distinguish between an ectopic and an absent vermis, the expression patterns of two Purkinje cell specific compartmentation antigens, zebrin II/aldolase C and the small heat shock protein HSP25, were analyzed in dreher cerebella. The data reveal that despite the reduction in volume and abnormal foliation of the cerebellum, the transverse zones and parasagittal stripe arrays characteristic of the normal vermis are present in dreher, but may be highly distorted. In dreher mutants with a severe phenotype, zebrin II stripes are fragmented and distributed non-symmetrically about the cerebellar midline. We conclude that although Purkinje cell agenesis or selective Purkinje cell death may contribute to the dreher phenotype, our data suggest that aberrant anlage patterning and granule cell development lead to Purkinje cell ectopia, which ultimately causes abnormal cerebellar architecture in dreher.

show abstract

Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene

Cited by 35 publications

References 22 publications

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

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

Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors

Purkinje cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher

Contact Info

Product

Resources

About