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22q11 Deletion Syndrome Provides Gene Suspects for Schizophrenia

16 November 2012. Two recent studies in mouse models of 22q11.2 deletion syndrome, a genetic predictor of schizophrenia, reveal mechanisms that could play a role in both illnesses. One study, published November 6 in Proceedings of the National Academy of Sciences, suggests that disrupted migration of parvalbumin neurons is due to lower levels of a chemokine receptor, CXCR4. A second paper, published October 10 in the Journal of Neuroscience, links reduced levels of microRNA DGCR4 to elevations in the calcium ATPase SERCA2 and an increase in hippocampal long-term potentiation in another model of 22q11 deletion syndrome, and also finds increased levels of SERCA2 in postmortem schizophrenia tissue.

22q11 deletion syndrome (22q11 DS), also known as DiGeorge syndrome, knocks out a 1.5 to 3 Mbase span of chromosome 22. This range of deletion lengths is associated with a variable clinical presentation that includes dozens of associated features, including learning impairments, craniofacial abnormalities, and cardiovascular defects. In addition, the genetic syndrome is highly associated with disorders of abnormal cortical circuitry such as autism and schizophrenia (Insel, 2010). In fact, 20-30 percent of 22q11 DS patients develop schizophrenia, and it’s estimated that 1 percent of schizophrenia patients carry the deletion (Bassett and Chow, 2008). Thus, studying 22q11 DS may yield important insights into the pathogenesis of schizophrenia.

Parvalbumin interneurons, 22q11 DS, and schizophrenia
Alterations in GABAergic interneurons and abnormal neuronal migration are hypothesized to play a role in 22q11.2 DS (Mori et al., 2011; Kiehl et al., 2009). Interneuron abnormalities, particularly in cells that express parvalbumin, are also well documented in schizophrenia (see SRF related news story; Fung et al., 2010). In the first study, led by Anthony-Samuel LaMantia of George Washington University in Washington, DC, researchers used the Large Deletion (LgDel) mouse model of 22q11 DS, in which they have previously shown that a redistribution of parvalbumin neurons is present (see SRF related news story), to look for a mechanism underlying this impairment.

In the current study, lead author Daniel Meechan and colleagues also observed a redistribution of parvalbumin neurons, but not other interneuron subtypes, in the LgDel mouse. This altered migration pattern was found to be cell-autonomous, that is, not regulated by the milieu around the cell. A reduction in the mRNA expression levels of several genes known to regulate interneuron migration was also observed. The authors narrowed in on one particular transcript—C-X-C chemokine receptor type 4 (CXCR4)—because it plays a cell-autonomous role in interneuron migration (Stumm et al., 2003).

In addition to lower mRNA levels, protein levels of CXCR4 are also reduced in the LgDel model. When CXCR4 was selectively reduced in LgDel mouse interneurons, the altered migratory phenotype of interneurons was enhanced, leading the authors to suggest that 22q11 DS “is in part a neuronal migration disorder in which diminished … gene dosage disrupts interneuron migration via a CXCR4-dependent mechanism.”

SERCA2, 22q11 DS, and schizophrenia
In a second study, from Stanislav Zakharenko’s lab at St. Jude Children’s Research Hospital in Memphis, Tennessee, researchers investigated a prior observation in a different 22q11 DS mouse model—an age-dependent increase in hippocampal long-term potentiation (LTP) and spatial memory impairment. The increase in LTP is also dependent on an elevation in SERCA2 (Earls et al., 2010), an ATPase that maintains calcium levels in the endoplasmic reticulum. By upregulating calcium levels in the cytoplasm, increased SERCA2 levels cause elevated neurotransmitter release, thereby enhancing LTP.

This mouse model, termed Df(16)1/+, contains hemizygous deletions in 23 genes on chromosome 16, homologous to the 22q11 DS region in humans. To determine the specific gene(s) involved in the elevated SERCA2 and enhanced plasticity phenotype, first author Laurie Earls and colleagues generated various mouse models with deletions in smaller regions of the Df(16)1 region, finding that only DGCR4 heterozygous (DGCR4+/-) mice replicated the age-dependent increase in LTP. This dovetails with evidence from the Karayiorgou/Gogos group at Columbia University, which also fingers DGCR4 as the main gene of interest in the deleted segment in terms of the neurobiological effects on the mice (see SRF related news story). DGCR4+/- mice also showed an upregulation in the level of SERCA2 in hippocampal synaptosomal preparations that was not observed in younger mice. In fact, inhibition of SERCA2 normalized LTP levels in DGCR4+/- slices.

Because DGCR4 is a gene involved in microRNA biogenesis, a process that negatively regulates protein translation, Earls and colleagues hypothesized that a loss of regulatory microRNAs underlies the elevated levels of SERCA2. Consistent with this idea, they observed a downregulation of several microRNAs in Df(16)1+ mice, including miR-25, -98, and -125. Expression of either miR-25 or miR-185 was able to reverse the increased LTP observed in the hippocampus of DGCR4+/- mice and significantly decrease SERCA2 protein levels.

Consistent with a role for SERCA2 in schizophrenia, protein levels of the ATPase were significantly increased in both the hippocampus and prefrontal cortex of subjects with schizophrenia. Although the authors did not measure microRNA levels in this tissue, their finding that the binding sites of miR-25 and miR-185 on SERCA2 are conserved between mouse and humans suggests that these microRNAs are “a potential mechanism for the observed SERCA2 protein overexpression in schizophrenia.”—Allison A. Curley.

References:
Earls LR, Fricke RG, Yu J, Berry RB, Baldwin LT, Zakharenko SS. Age-Dependent MicroRNA Control of Synaptic Plasticity in 22q11 Deletion Syndrome and Schizophrenia. J Neurosci . 2012 Oct 10 ; 32(41):14132-44. Abstract

Meechan DW, Tucker ES, Maynard TM, Lamantia AS. CXCR4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome. Proc Natl Acad Sci U S A . 2012 Oct 22. Abstract

Comments on News and Primary Papers


Primary Papers: Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome.

Comment by:  Bryan Roth, SRF Advisor
Submitted 26 October 2012
Posted 30 October 2012
  I recommend this paper

This is an interesting and elegant study which clarifies potential mechanisms responsible for the myriad psychiatric and cognitive actions of 22q11.2 deletions.

View all comments by Bryan Roth

Comments on Related News


Related News: 22q11 and Schizophrenia: New Role for microRNAs and More

Comment by:  Linda Brzustowicz
Submitted 21 May 2008
Posted 21 May 2008

While some have expressed frustration over the lack of clear reproducibility of linkage and association findings in schizophrenia, the importance of the chromosome 22q11 deletion syndrome (22q11DS) as a real and significant genetic risk factor for schizophrenia has often been overlooked. While the deletion syndrome is present in a minority of individuals with schizophrenia (estimates of approximately 1 percent), presence of the deletion increases risk of developing schizophrenia some 30-fold, making this one of the clearest known genetic risk factors for a psychiatric illness. As multiple genes are deleted in 22q11DS, it can be a challenge to determine which gene or genes are involved in specific phenotypic elements of this syndrome.

The May 11, 2008, paper by Stark et al. highlights the utility of engineered animals for dissecting the individual effects of multiple genes within a deletion region and provides an important clue into the mechanism likely responsible for at least some of the behavioral aspects of the phenotype. While some may argue about the full validity of animal models of complex human behavior disorders, these systems do have an advantage in manipulability that cannot be achieved in work with human subjects. A key feature of this paper is the comparison of the phenotype of mice engineered to contain a 1.3 Mb deletion of 27 genes with mice engineered to contain a disruption of only one gene in the region, DGCR8. The ability to place both of these alterations on the same genetic background and then do head-to-head comparisons on a number of behavioral, neuropathological, and gene expression assays allows a clear assessment of which components of the mouse phenotype may be attributed specifically to DGCR8 haploinsufficiency. Perhaps not surprisingly, DGCR8 seems to play a role in some, but not all, of the behavioral and neuropathological changes seen in the animals with the 1.3 Mb deletion. The fact that the DGCR8 disruption was able to recapitulate certain elements of the full deletion in the mice does raise its profile as an important candidate gene for some of the neurocognitive elements of 22q11DS, and makes it a potential candidate gene for contributing to schizophrenia risk in individuals without 22q11DS.

Also of great interest is the known function of DGCR8. While the gene name simply stands for DiGeorge syndrome Critical Region gene 8, it is now known that this gene plays an important role in the biogenesis of microRNAs, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. As miRNAs have been predicted to regulate over 90 percent of genes in the human genome (Miranda et al., 2006), a disruption in a key miRNA processing step could have profound regulatory impacts. Indeed, as reported in the Stark et al. paper and elsewhere (Wang et al., 2007), homozygous deletion of DGCR8 function is lethal in mice. What perhaps seems to be the most surprising result is that haploinsufficiency of DGCR8 function does not induce a more profound phenotype, given the large number of genes that would be expected to be affected if miRNA processing were globally impaired. The Stark et al. paper determined that while the pre-processed form of miRNAs may be elevated in haploinsufficient mice, perhaps only 10-20 percent of all mature miRNAs show altered levels, suggesting that some type of compensatory mechanism may be involved in regulating the final levels of the other miRNAs. Still, the 20-70 percent decrease in the abundance of these altered miRNAs could have a profound effect on multiple cellular processes, given the regulatory nature of miRNAs. In the context of the recent evidence for altered levels of some miRNA in postmortem samples from individuals with schizophrenia (Perkins et al., 2007), the Stark et al. paper adds further support for studying miRNAs as potential candidate genes in all individuals with schizophrenia, not just those with 22q11DS. This paper should serve as an important reminder of how careful analysis of a biological subtype of a disorder can reveal important insights that will be relevant to a much broader set of affected individuals.

References:

1. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 May 11; Abstract

2. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006 Sep 22;126(6):1203-17. Abstract

3. Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007 Mar 1;39(3):380-5. Abstract

4. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007 Jan 1;8(2):R27. Abstract

View all comments by Linda Brzustowicz

Related News: Putting 2 and 2 Together—Chromosomal Deletions and Neurodevelopment in Schizophrenia Susceptibility

Comment by:  Brian Morris
Submitted 5 October 2009
Posted 5 October 2009

The dramatically increased risk of schizophrenia associated with velocardiofacial/DiGeorge syndromes (VCFS/DGS) can potentially provide us with a unique insight into the causes of the disease. This study is interesting in that it provides further evidence that reduced levels of expression of the genes encoded in this short region of chromosome 22 are sufficient to cause neurodevelopmental impairments in cerebrocortical neurons. It is worth remembering, as noted above, and as emphasized by the authors, that VCFS/DGS are associated with increased risk of a number of mental health problems with a neurodevelopmental component, not just schizophrenia. In fact, the cortical abnormality reported in this paper that can be specifically associated with schizophrenia (altered parvalbumin neuron distribution) is really subtle. Nevertheless, the study suggests that reduced expression of these few genes on chromosome 22 may be sufficient to cause cortical parvalbumin neuron dysfunction. In turn, this provides some support for the theory that cortical GABA interneuron impairments are an early event in the etiology of schizophrenia, and not simply a consequence of the cortical dysfunction arising from other causes.

The number of genes in the VCFS/DGS deletion region is small, and studies using gene-specific knockouts can provide further insight into the mechanisms leading to altered cortical function in schizophrenia.

View all comments by Brian Morris