Institute of Pathology, University Hospital Tubingen, Germany
NKX2-1 also plays an important role in the endocrine system: it regulates the expression of the thyroid-specific genes thyroglobulin, thyroid peroxidase, thyrotropin receptor and sodium-iodide-symporter, therefore being crucial for proper thyroid hormone synthesis.
Deletion of NKX2-1 in differentiated neurons of the hypothalamus in mice causes delayed puberty, reduced reproductive capacity and a shorter reproductive span in female mice, suggesting that NKX2-1 plays an important role in juvenile and adult endocrine function.
During embryonic and fetal development, NKX2-1 is active in various organs, especially lung, thyroid and brain.
As a crucial factor for lung development, NKX2-1 is expressed in the ventral foregut endoderm at a very early stage functioning as a signal which is essential for specification of a pulmonary cell fate instead of a liver cell fate. At a later stage, NKX2-1 is critical to the formation of distal pulmonary structures (whereas proximal lung differentiation is NKX2-1-independent), a function in which it is inhibited by TGF-beta.
In addition to that NKX2-1 regulates surfactant protein genes that are important for the development of alveolar stability at birth. It induces SP-A gene expression in fetal lung type II cells through increased binding of NKX2-1 (mediated by cAMP) and the NFkappa-B proteins p50 and p65. Supporting the notion of NKX2-1-dependent SP-expression, lung and associated respiratory dysfunction in neonates caused by SP-B-deficiency are partly induced by down-regulation of NKX2-1. The main therapeutical option, prenatal glucocorticoid treatment, induces the expression of NKX2-1. NKX2-1 regulates expression of uteroglobin-related protein-1 and claudin-18 during lung development.
During thyroid gland organogenesis NKX2-1 is expressed in the ultimobranchial body (UBB) and in the thyroid diverticulum. It is important for the survival of UBB-cells and eventually their dissemination into the thyroid diverticulum and for the formation of the UBB-derived vesicular structure. Pendrin and thyroglobulin are downstream targets of NKX2-1 during thyroid differentiation. The transactivational activity of NKX2-1 during thyroid development can be inhibited by NKX2-5.
In the course of brain development, NKX2-1 expression is found in both telencephalic and diencephalic domains. It cooperates with Gsh2 to pattern the ventral telencephalon. Lack of functional NKX2-1 protein in neurons impairs developmental differentiation and organization of basal ganglia and basal forebrain. NKX2-1 upregulates the transcription of nestin, an intermediate filament protein expressed in multipotent neuroepithelial cells, by direct binding to a HRE-CRE-like site (NestBS) within a CNS-specific enhancer, which indicates that nestin might be at least one of the effectors of NKX2-1 during forebrain development.
NKX2-1 expression occurs in neurons of the arcuate nucleus of the hypothalamus and in glia cells (tanycytes) in neonatal and adult mice, as well as in fetal and adult pituicytes suggesting that NKX2-1 is essential for proper development of the hypothalamus. Lack of NKX2-1 causes aberrant trajectory of the dopaminergic pathway in the developing hypothalamus (mouse-model), development of GABAergic and cholinergic neurons is also impaired in NKX2-1 defective mice. Furthermore, NKX2-1 regulates the specification of oligodendrocytes and controls the postmitotic migration of interneurons originating in the medial ganglionic eminence to either the cortex (downregulation of NKX2-1) or the striatum (maintenance of NKX2-1 expression and thus direct transcriptional activation of neuropilin-2, a guidance receptor in postmitotic cells). By directly activating Lhx6 during embryonic development NKX2-1 plays an essential role for the specification of cortical interneurons which express parvalbumin or somatostatin.
In accordance with the findings concerning the role of NKX2-1 in the development of the above-mentioned organs, NKX2-1-defective mice die at birth due to a characteristic set of malformations and functional impairments: hypoplastic lungs and insufficient surfactant production, defective hypothalamus, absence of thyroid and pituitary gland, delayed development of dopaminergic, GABAergic and cholinergic neurons.
A heterozygous substitution at position 1016 in the coding sequence (C → T) leads to a mutant NKX2-1 protein (A339V) and can contribute to a predisposition for multinodular goiter and papillary thyroid carcinoma.
For other heterozygous NKX2-1 mutations in humans, phenotypes vary widely.
Thyroid dysfunction ranges from mild hypothyrotrophinaemia to severe congenital hypothyroidism due to thyroid hypoplasia or even agenesis. Implication of the lung ranges from a slight increase in pulmonary infections to severe neonatal respiratory distress syndrome.
Homozygous NKX2-1 mutations in humans are probably not viable.
Theresia Wilbertz ; Sebastian Maier ; Sven Perner
NKX2-1 (NK2 homeobox 1)
Atlas Genet Cytogenet Oncol Haematol. 2010-04-01
Online version: http://atlasgeneticsoncology.org/gene/44015/nkx2-1