Abstract
Schizophrenia is a highly heritable disorder with diverse mental and somatic symptoms. The molecular mechanisms leading from genes to disease pathology in schizophrenia remain largely unknown. Genome-wide association studies (GWASs) have shown that common single-nucleotide polymorphisms associated with specific diseases are enriched in the recognition sequences of transcription factors that regulate physiological processes relevant to the disease. We have used a “bottom-up” approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. NKX2-1 is selectively expressed from prenatal development to adulthood in the brain, thyroid gland, parathyroid gland, lungs, skin, and enteric ganglia, and has key functions at the interface of the brain, the endocrine-, and the immune system. In the developing brain, NKX2-1-expressing progenitor cells differentiate into distinct subclasses of forebrain GABAergic and cholinergic neurons, astrocytes, and oligodendrocytes. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses. NKX2-1 interacts with a number of genes identified as susceptibility genes for schizophrenia. We suggest that NKX2-1 may lie at the core of several dose dependent pathways that are dysregulated in schizophrenia. We correlate the symptoms seen in schizophrenia with the temporal and spatial activities of NKX2-1 in order to highlight promising future research areas.
Highlights
Schizophrenia is a complex disorder that affects approximately 1% of the world’s population over the age of 18
An aberrant distribution of interstitial cells and reduced reelin mRNA levels have been detected in the prefrontal cortex and in the hippocampal formation (Akbarian et al, 1996; Kirkpatrick et al, 2003; Eastwood and Harrison, 2006). These findings may suggest that NKX2-1-derived Cajal-Retzius and interstitial cells are dysfunctional in patients with schizophrenia, it is important to bear in mind that these
This opens the possibility that abnormalities seen in early visual processing in schizophrenia might be influenced by Nkx2-1 expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) (Koychev et al, 2011; Khosravani and Goodarzi, 2013; Nunez et al, 2014; Lee et al, 2016)
Summary
We have used a “bottom-up” approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses.
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