Group3: LIM homeobox transcription factor 1 alpha (Lmx1a) - Jamie, Gayathri & Emma

Introduction

Lmx1a was initially found to be expressed in insulin-producing beta cells in the pancreas. The transcription factor contains one homeobox DNA-binding domain and two LIM zinc-binding domains, which are conserved between humans and mouse. The homedomain protein acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter.

(Source: Chizhikov et al, 2004)

Mutations in the dreher locus produce neurological and skeletal abnormalities, inner ear defects, and belly spotting. Deafness and hypoplasia of Mullerian duct derivatives are also reported for some alleles (MGI). Using positional cloning, Millonig at el. (2000) reported that defects in Lmx1a are the cause of the spontaneous neurologic mutant mouse, called 'dreher' and results from a failure of the roof plate to develop. Lmx1a is expressed in the roof plate along the neuraxis during development of the central nervous system and is required for the development of the roof plate and, in turn, for specification of dorsal cell fates in the central nervous system and developing vertebra.

In-situ hybridization of Lmx1a in the developing nervous system of a E11.5 mouse. Note that Lmx1a ia strongly expressed in the midbrain (where the dopamine neurons are located), and the roof plate. (Source: Visigene, UCSC genome browser)

The importance of Lmx1a as a determinant for the development of dopamine neurons was established when Andersson et al. (2006) showed that Lmx1a was necessary and sufficient to trigger dopamine cell differentiation. Expression of Lmx1a in embryonic stem cells also resulted in robust generation of dopamine neurons with midbrain identity. These embryonic-stem cell derived neurons express all the known markers of the midbrain dopaminergic neurons and possess similar electrophysiological properties as bona fida dopamine neurons. Such neurons effectively innervate the striatum when transplanted into the mouse model of Parkinson's disease (Friling S et al, 2009).

Embryonic stem cell-derived dopamine neurons (A) are large and elongated like that of the bona fida dopamine neurons (B), and express all the known markers (C to J). (Source: Friling S et al, 2009)

Gene information

Protein Information

Homedomain

The 'homeobox' is a protein domain of 60 amino acids conserved in many other animals, including vertebrates. This domain binds DNA through a helix-turn-helix type of structure. Some of the proteins which contain a homeobox domain play an important role in development. Most of these proteins are known to be sequence specific DNA-binding transcription factors.

LIM domain

In the LIM domain, there are seven conserved cysteine residues and a histidine. The LIM domain binds two zinc ions. LIM does not bind DNA, rather it seems to act as interface for protein-protein interaction.

HomoloGene Results

Pairwise Alignment Score

Relevance to Disease

(Source: HapMap genome browser)

Type 2 Diabetes (T2DM? )

Since Lmx1a has been shown to activate insulin gene transcription, Thameem et al (2002) analyzed Lmx1a as a candidate genetic cause of Type 2 diabetes in Pima Indians. They identified seven SNPs (single nucleotide polymorphisms) but did find any association of T2DM? with any SNPs.

Parkinsons's Disease (PD)

The disease hallmark of Parkinson's Disease is the gradual death of dopamine neurons in the midbrain. Researchers are still unclear about the exact cause of Parkinson's Disease. Hence, the discovery of the importance of the Lmx1a gene in the development of dopamine neurons led Bergmann et al (2009) to look into the relationship of polymorphisms to PD.

They investigated if genetic variation in Lmx1a differs between normal individuals and patients with Parkinson's disease. A total of 46 SNPs covering a genomic region of 186.2 kb including the Lmx1a gene were identified for genotyping using the Hap Map database (population CEU:Utah residents with ancestry from northern and western Europe). Out of the 33 SNPs genotyped in the study, three SNPs in Lmx1a were found to be weakly associated with Parkinsons's disease.

References

1. Millonig, J. H.; Millen, K. J.; Hatten, M. E. : The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature 403: 764-769, 2000.
2. Andersson, E.; Tryggvason, U.; Deng, Q.; Friling, S.; Alekseenko, Z.; Robert, B.; Perlmann, T.; Ericson, J. : Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124: 393-405, 2006.
3. Chizhikov VV, Millen KJ. Mechanisms of roof plate formation in the vertebrate CNS. Nat Rev Neurosci. 10: 808-812, 2004.
4. Friling S; Andersson E; Thompson LH; Jonsson ME; Hebsgaard JB; Nanou E; Alekseenko Z; Marklund U; Kjellander S; Volakakis N; Hovatta O; El Manira A; Bjorklund A; Perlmann T; Ericson J. Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proc Natl Acad Sci U S A 106(18):7613-8, 2009.
5. Bergman O, Håkansson A, Westberg L, Belin AC, Sydow O, Olson L, Holmberg B, Fratiglioni L, Bäckman L, Eriksson E, Nissbrandt H. Do polymorphisms in transcription factors Lmx1a and Lmx1b influence the risk for Parkinson's disease? J Neural Transm. 116(3):333-8. Epub 2009 Feb 3.
6. Developmental Biology. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.box.2019
7. Thameem F, Wolford JK, Wang J, German MS, Bogardus C, Prochazka M. Cloning, expression and genomic structure of human LMX1A, and variant screening in Pima Indians. Gene 290(1-2):217-25, 2002.

Databases referred to

NCBI
UCSC genome browser
Mouse Genome Informatics (MGI)
Prosite
HapMap