A Role for the Transcription Factor Nk2 Homeobox 1 in Schizophrenia: Convergent Evidence from Animal and Human Studies

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.

Keywords: GABA; NKX2-1; Schizophrenia; brain; brain development; calcium; immune system; thyroid hormones.

Figure 1

Early brain development and Nkx2-1 expression in the early embryonic brain. (A) Brain vesicles and divisions in the mammalian brain corresponding to gestational day 33 in humans. (B) Nkx2-1 is expressed as a longitudinal band in the ventral secondary prosencephalon from the rostral pallidum to the caudal hypothalamic area (rodent brain E15, corresponding to gestational day 49 in humans). (C) Future basal ganglia develop from subcortical parts of the telencephalon (“subpallium”). The striatum develops from the lateral ganglionic eminence, and pallidum from the medial ganglionic eminence. (D) Side view illustrating the medial, lateral, and caudal ganglionic eminences.

Figure 2

Schematic illustration of information flow through the direct pathway in cortical-basal ganglia-thalamocortical circuits. Information from the motor cortex passes to the dorsal striatum, globus pallidus, ventral lateral thalamus, and back to the motor cortex (red line). Information from the anterior cingulate and the prefrontal cortex passes to the ventral striatum, ventral pallidum, mediodorsal thalamus, and back to the anterior cingulate and prefrontal cortex (blue line).

Figure 3

Nkx2-1 is expressed in a subcortical neuroendocrine network involved in social behavior and reproduction in the rodent brain. The posterodorsal medial amygdala, ventral lateral septum, and posteromedial bed nucleus of the stria terminalis, provide major inputs to the hypothalamic neuroendocrine effector system. Neuroendocrine hypothalamic nuclei provide feedback to the posterodorsal medial amygdala, and the ventral lateral septum.

Figure 4

Nkx2-1 expression in mature amygdala nuclei, and the stria terminalis in the rodent brain is restricted to subnuclei involved in social, reproductive, and fear-defense responses. (A) Expression occurs in the posterodorsal and posteroventral medial nuclei, the ventral part of the anterior nucleus, the medial part of the central nucleus, the medial extended amygdala, and the posteromedial bed nucleus of the stria terminalis. (B) Details of the medial amygdala nucleus. Nkx2-1 is expressed by 70% of neurons in the posterodorsal medial nuclei (social-reproductive) and 30% of neurons in the posteroventral medial nuclei (fear-defense), suggesting different roles for NKX2-1 in the two sets of responses.