Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

Abstract

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS

“…For instance, IFN-treated fetal murine neuroblast cultures developed a differentiated neuronal population associated with the expression of mature neurofilament proteins (Plioplys, 1988). In addition, JAK-STAT signaling downstream of many cytokines, such as type I IFN and IL-2, IL-6, IL-10, and TNF-a (Murray, 2007), plays a critical role in various brain developmental pathways, especially in promoting astrogliogenesis (Lee et al, 2016). Astrocytes, in turn, are known to substantially contribute to CNS development by controlling synaptogenesis and axon guidance factors (Chung et al, 2015b).…”

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

“…In vivo studies showed that overexpression of STAT3 in the neocortex of DS mice (Ts1Cje) enhanced astrogliogenesis [68], whereas its knockout inhibited the astroglial fate in mouse NSCs [69]. Additionally, it was reported that IL-6 in DS children and IFN-γ in embryonic trisomy 16 mouse brains (Ts16, a model used for human trisomy 21 (DS)), were increased respectively [70,71], both of which are capable of activating the STAT3 pathway [72]. Indeed, neonate DS mice (Ts65Dn) exhibited hyperactivation of STAT3 in the hippocampus [73].…”

“…Notch signaling was shown to cross-talk with JAK-STAT [72] and SHH signaling pathways [93], thereby inducing gliogenic shift during brain development. Mediated by binding of ligands such as delta-like protein 1 (Dll1), cleavage of the transmembrane receptor Notch by γ-secretase is initiated.…”

Moving Targets: Monitoring Target Trends in Drug Discovery by Mapping Targets, GO Terms, and Diseases

“…In contrast, Janus kinases are not linked to breast cancer, but to intellectual disability (which in return is not linked to cannabinoid receptors). The association between Janus kinases and intellectual disability is a quite recent finding since the role of the JAK-STAT pathway in neuronal differentiation and gliogenesis is only insufficiently understood to date [50].…”