Down Syndrome Abstract
of the Month:
Nov 2003
Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation.
Hammerle B, Carnicero A, Elizalde C, Ceron J, Martinez S, Tejedor FJ
Eur J Neurosci. 2003 Jun;17(11):2277-86
Instituto de Neurociencias, CSIC and Universidad Miguel Hernandez, San Juan, 03550 Alicante, Spain.
Abstract:
The Minibrain (Mnb) gene belongs to a new protein kinase family, which is evolutionarily conserved, and probably plays several roles during brain development and in adulthood. In Drosophila, mnb is involved in postembryonic neurogenesis and in learning/memory. In humans, MNB has been mapped within the Down syndrome critical region of chromosome 21 and is overexpressed in the Down syndrome embryonic brain. It has been widely proposed that MNB is involved in the neurobiological alterations associated with Down syndrome. Nevertheless, little is known about the functional role that MNB plays in vertebrate brain development. We have recently shown [Hammerle et al. (2002) Dev. Biol., 246, 259-273] that in early vertebrate embryos, Mnb is transiently expressed in neural progenitor cells during the transition from proliferating to neurogenic divisions. Here we have studied in detail a second wave of Mnb expression, which takes place in the brain of intermediate and late vertebrate embryos. In these stages, MNB seems to be restricted to certain populations of neurons, as no consistent expression was detected in astroglial or oligodendroglial cells. Interestingly, MNB expression takes place at the time of dendritic tree differentiation and is initiated by a transient translocation from the cytoplasm to the nucleus. Afterwards, MNB protein is transported to the growing dendritic tree, where it colocalizes with Dynamin 1, a putative substrate of MNB kinases. We propose that MNB kinase is involved in the signalling mechanisms that regulate dendrite differentiation. This functional role helps to build a new hypothesis for the implication of MNB/DYRK1A in the developmental aetiology of Down syndrome neuropathologies.
My comments:
This is the latest in a body of work on the human dyrk1A gene, all of which started in 1995. This is potentially quite a big deal for research in Down syndrome, and I wanted to use this paper to review what parents should know about this gene and the ongoing research.In the early 1990s, researchers working on the fruit fly (drosophila) isolated a gene that when it didn't work, caused the fly to have smaller than normal brains and impaired learning. The gene was called the mnb gene, short for "minibrain." Researchers also found similar genes in mice and rats. Researchers isolated the protein that this gene made, and renamed it the dyrk gene as an acronym based on its amino acid construction.In 1996, researchers found a human version of the gene on the 21st chromosome, and in the area known as the "Down syndrome critical region." These researchers speculated that too much or too little of the protein this gene made interfered with development of the brain, and could play a crucial role in children with DS.
At the exact same time, another group of researchers were working with specifically designed mice that were bred to carry part of the human 21st chromosome. I had abstracted this study back when it was published, and you can read the details of it here. But the bottom line of that study was that the mice with the human dyrk gene had severe learning deficits. The two studies strongly implicated this gene as a major source of learning difficulties in children with DS.
In 2001, another group of researchers developed special mice that carried the human dyrk gene. These mice had delayed development of the brain, decreased motor skill acquisition and hyperactivity, and a significant impairment in spatial learning and reference memory. And earlier this year, still another group of researchers isolated the gene in a nematode; this paper was significant in that the researchers felt that the overexpression of the mnb gene in the nematode could be reversed.
And now, to the above article:
The above paper looked at mnb gene expression in chickens. This was an extremely detailed work, looking for signs of mnb expression in late embryonic development. The authors found mnb expressed specifically in brain cells and not in supporting brain tissue cells. The protein produced by the nmb gene correlated well with the action of formation of the dendritic tree of the brain cells. The "dendritic tree" is the area of the brain cell where multiple connections with other brain cells are made. In children withe Down syndrome, the dentritic tree is smaller than normal and has abnormal formations. This malformation of the dendritic tree may well be a major factor in the cognitive difficulties seen in people with DS.
Now the question is whether this information might be put to good use. Some researchers believe it can. News items from the LA Times and the BBC the end of October 2003 reported that the new Stanford Center for DS Research is going to be studying this very idea. First, we have to see whether the gene can be turned off or its expression of its protein reduced. Then, we have to see what affect that action would have on brain development. These would obviously be done on trisomy mice first. Only then can we imagine that this might be beneficial to infants or children with DS.
I have put copies of the two news reports here.
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