Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development
Section snippets
Disorders of cortical circuit development: finding a model
The inescapable causal relationship between disrupted developmental mechanisms and the pathology of human developmental disorders has proven difficult to evaluate rigorously in patients, especially for disorders of cortical circuit development like autism spectrum disorder (Geschwind and Levitt, 2007) (ASD), attention deficit/hyperactivity disorder (Shaw et al., 2010) (ADHD) and schizophrenia (SCZ; Insel, 2010). This difficulty reflects the timing of developmental pathogenesis, which occurs
Syndromes and spectrums: core features and variability in 22q11DS
22q11DS, like most developmental disorders, has a set of common features traditionally recognized as the clinical “core” of the syndrome, and several other features that are seen more variably in subsets of patients. Together, these features define a phenotypic spectrum of 22q11DS (Fig. 1). The core syndromic features include conotruncal cardio-vascular malformations, often focused on derivatives of the fourth pharyngeal arch artery (Botto et al., 2003, Ryan et al., 1997); characteristic
Genomic mechanisms of 22q11.2 deletion
The causal relationship between 22q11.2 deletion and the spectrum of cardiac, craniofacial, immune and behavioral disorders recognized clinically as DiGeorge Syndrome (Kirkpatrick and DiGeorge, 1968) became clear in the late 1980s and early 1990s, when the typical and minimal critical deleted regions of hChr22q11.2 were identified in DiGeorge Syndrome patients (Cannizzaro and Emanuel, 1985, Driscoll et al., 1992, Halford et al., 1993, Kelly et al., 1993; Fig. 2). Subsequent efforts in the 1990s
From clinic to cage: 22q11DS cardiac phenotypes in mouse genetic models
Cautious comparisons of human disease features with parallel phenotypes in a genomically accurate animal model are key for assessing whether the model can be used to understand disease pathogenesis. Thus, a critical test of the relevance of mouse genomic models for 22q11 deletion is their capacity to reproduce—or at least approximate—diagnostic clinical features of 22q11DS. One of the most important clinical features of the syndrome—and one that often proved fatal prior to improvements in
Dysphagia in 22q11DS humans and mice: compromising body and brain
It is not clear whether apparent conservation of morphogenetic mechanisms in the hearts of humans and mice as well as their disruption by diminished 22q11 gene dosage extends to the brains of humans and mice—especially since the most noted brain-related disease phenotypes in 22q11DS, ASD, ADHD and SCZ, reflect disruptions in complex human behavioral capacities whose murine equivalents—if they exist—are uncertain (Crawley, 2012). Thus, as a further assessment of the utility of 22q11DS mouse
22q11DS: a paradigmatic disorder of cortical circuit development?
Parallels between 22q11DS cardiac and craniofacial anomalies, as well as clinical complications like dysphagia and mechanistically defined developmental phenotypes in mouse models of 22q11 deletion raise an essential question: can developmental pathogenesis of disorders of cortical circuit development including ASD, ADHD and SCZ, associated with 22q11DS, also be defined using mutant mice that approximate key genomic lesions in 22q11DS? The first essential step in such an enterprise is to
Parallel cortical pathology in 22q11DS
These cytological, structural and functional studies, in broadly defined “non-syndromic” ASD, ADHD and SCZ patients (i.e. those without a specific genetic or clinical diagnosis of an identified developmental syndrome like 22q11DS) suggest that the cytology, circuitry and function of association cortices should be disrupted in 22q11DS patients, in register with the high frequency of ASD (Niklasson et al., 2009), ADHD (Niklasson et al., 2009, Tang et al., 2014) and SCZ (Bassett et al., 2005,
Can 22q11 genes influence cortical circuit development?
Diminished dosage of 22q11 genes is likely to compromise cortical development if one, a few, or most of the deleted 22q11 genes are expressed in the developing cortex. Thus, to formulate and test hypotheses, it is first necessary to establish a thorough 22q11 gene expression profile throughout pre- and post-natal cortical development. We compared the general expression of 22q11 genes in developing human cortex to that of orthologous genes in the developing murine cortex as an initial test of
Cortical neurogenesis is disrupted by 22q11 deletion
The expression of several 22q11 genes implicated in cell cycle regulation in the VZ and SVZ during cortical neurogenesis raised the possibility that 22q11 deletion might contribute to disorders of cortical connectivity by altering cortical neurogenesis, especially for projection neurons that are derived from cortical progenitors resident in the VZ and SVZ (Molnar and Clowry, 2012). Cortical progenitor populations in the VZ and SVZ are diverse. There are two broad classes: apical/radial glial
Cortical interneuron migration is disrupted by 22q11 deletion
Morphologically and biochemically diverse classes of GABAergic interneurons (Monyer and Markram, 2004), whose local connections establish appropriate inhibitory/excitatory balance in cortical circuits (Markram et al., 2004) are also thought to be altered in ASD, ADHD, and SCZ (Chattopadhyaya and Cristo, 2012, Inan et al., 2013, Lewis et al., 2005). The opportunities for disrupting the genesis, migration and differentiation of GABAergic interneurons are manifold: these neurons are generated in a
One or many: how do 22q11 genes alter cortical development?
A significant challenge associated with CNV disorders is determining whether key syndromic phenotypes—like disrupted cardiovascular or cerebral cortical development—reflect the consequences of diminished dosage of one single gene in the deleted region (thus, true haploinsufficiency) or interactions between diminished dosage of multiple genes. Our data on general diminished dosage of multiple brain expressed mouse 22q11 gene orthologues (with only one instance of translational dosage
22q11 deletion, disrupted cortical development, and behavior
Our observations show that the genesis and differentiation of cortical layer 2/3, especially in association cortical regions, is selectively compromised by diminished 22q11 gene dosage. These changes modify the mature organization of projection neurons and interneurons in layer 2/3, and may contribute to disrupted cortical connections, information processing, and behavior in 22q11DS. Developmental disruptions caused by 22q11 deletion result in phenotypes similar to adult pathological changes
Models and hypotheses: 22q11DS disrupts association cortex circuit development
The increased incidence of developmental disorders (2014) and the ongoing challenges of managing these illnesses (Insel, 2010) underline an urgent need for new insight into diseases caused by disrupted cortical development and function. Human genetic analyses and non-invasive imaging approaches, integrated with careful behavioral and clinical assessment, has provided a strong foundation for understanding hereditary risk, neuropathology and behavioral consequences of ASD, ADHD and SCZ. These
Modeling models: a translational foundation for understanding disorders of cortical circuit development
Disorders of cortical circuit development are likely to remain among the most costly and difficult to manage chronic diseases in the foreseeable future. While currently available treatments—both pharmacological and cognitive—offer some relief from symptoms (Lai et al., 2014, Miyamoto et al., 2012), there is a general lack of therapies that prevent symptoms, or correct key deficits. The variability seen among non-syndromic patients with ASD, ADHD, SCZ and related disorders of cortical circuit
Acknowledgements
We thank Chiara Manzini and Sally Moody for helpful comments on the manuscript. This work was supported by National Institute of Child Health and Human Development Grants HD042182 and HD029178, NIDCD (DC011534), NICHD intellectual and developmental disabilities research center (P30HD040677), the Silvio M. Conte Grant (MH64065) and a Simons Foundation grant (SFARI 306796). Confocal microscopy and ISH analysis used University of North Carolina Neurosciences Center core facilities (NS031768) and
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Transcriptional coregulator Ess2 controls survival of post-thymic CD4<sup>+</sup> T cells through the Myc and IL-7 signaling pathways
2022, Journal of Biological ChemistryCitation Excerpt :These results show that the Ess2 protein associates with several transcription factors to regulate their activity, which may also contribute to Ess2-specific immune regulation. Several mouse models of 22q11DS exist (31), including 22q11.2 deletion heterozygous mice and 22q11DS-associated transgenic mice (32–34). A recent study has reported the generation of a CRISPR-Cas-mediated deletion of 22q11DS (35).
22q11.2 deletion syndrome: Future directions
2022, The Chromosome 22q11.2 Deletion Syndrome: A Multidisciplinary Approach to Diagnosis and Treatment22q11.2 deletion syndrome: Setting the stage
2022, The Chromosome 22q11.2 Deletion Syndrome: A Multidisciplinary Approach to Diagnosis and Treatment