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.

Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin

“…Taking the literature into account, our current data suggest that the HPV vaccine may disrupt signaling pathway mediated by Nkx2.1 that are expressed in the hypothalamic region. We studied on the neurotransmitters production in order to corroborate pathophysiological correlation of Nkx2.1, since some studies indicated the abnormalities of several neurotransmitters production in Nkx 2.1 deficient-mice in early development42, and also in adult mice3538. We found similar phenotype of neurotransmitters production in group 4 mice including increase of dopaminergic neurons and reduced GABAergic neurons (Fig.…”

“…Nkx2.1 is also known to be expressed in the hypothalamic region and periventricular areas from early phase of development to adult35. Further, Nkx2.1 is thought to play roles in puberty and reproductive function and schizophrenia353738. In humans, Nkx2.1 gene mutations can cause benign hereditary chorea (BHC)3940, a disease affecting the brain, lungs and thyroid.…”

Chromatin dynamics enable transcriptional rhythms in the cnidarian Nematostella vectensis

“…Another example is the homeobox motifs, enriched in both the LD and DD treatments, as well as around genes from clusters 1, 3, 4 and 5. Homeobox factors, in particular members of the NK homeobox gene family, with motifs enriched in both treatments, have been shown to contribute to rhythmic regulatory processes in mammals [25]. Within cluster 5, 16 cyclic genes, including NvClock (a core component of the circadian clock machinery), contain the binding motif of C/EBP in their accessible promoter region (Fig 3C and S3 Table).…”

“…Another interesting finding is the presence (or absence) of homeobox-related TFs in rhythmic genes regulation. The identified motifs were enriched with NK Homeobox and HOX family motifs–some of which contribute to rhythmic regulatory processes [25] including CUX1 , LIN-39 ( HOX3A ), caudal and CDX2 (Caudal-Type Homeobox 2). Interestingly, caudal has also been identified (in gene cluster 3) and previously reported as a synchronizer of locomotor activity in crayfish [39].…”

Meaning and Matter in Psychiatry: A Historical View and New Approach

“…New journals are dedicated to molecular psychiatry, for instance "Molecular Psychiatry" [18]. Mental illnesses are conceptualised as multi-organ, systemic illnesses involving a myriad of intra-and extracellular mechanisms [19,20]. The ambition to identify causal mechanisms connecting symptoms or syndromes with a neurobiological substrate remains central to the paradigm we are currently experiencing.…”