The role of TGF-β superfamily signaling in neurological disorders

Abstract

The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

Keywords: BMP; GDFs; TGF-β; cognitive disease; neurodegenerative disease; neurons.

Figure 1.

Signal transduction by TGF-βs and BMPs TGF-β and BMP ligands induce formation of heteromeric complex between specific Type II and Type I receptors. The Type II receptors transphosphorylate the Type I receptors and activate the Type I receptor kinases. The Type I receptor transmits the signal to the cell by phosphorylating receptor-regulated (R)-Smads, which form heteromeric complexes with Smad4 (common (Co)-Smad) and translocate in the nucleus where by interacting with other transcription factors regulate gene transcriptional responses, chromatin remodeling, and/or control of microRNA processing [‘canonical (or Smad-dependent) pathway’]. Inhibitory (I)-Smads; Smad6 and Smad7 inhibit activation of R-Smads. In addition, the activated Type I receptors can activate ‘non-canonical (or non-Smad) pathway’ via different effectors, such as extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), p38, Rho, phosphoinositide 3-kinase (PI3K), transforming growth factor beta-activated kinase 1 (TAK1), p21 (RAC1) activated kinase 1 (PAK1), and LIM domain kinase 1 (LIMK1). CR and TF stand for chromatin remodeling protein and transcription factor, respectively.

Figure 2.

Roles of TGF-βs and BMPs in the neural development and function Signaling by the TGF-β family is required for proper neural development and function. Both inductive (green arrows) and inhibitory signals (red lines) of different ligands at various steps of neural differentiation are shown. CNS and PNS stand for central nervous system and peripheral nervous system, respectively.