ABSTRACT
The thalamus or "inner chamber" of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity.
Subject(s)
Thalamus/physiology , Animals , Computational Biology , Female , Gene Expression Regulation, Developmental , In Situ Hybridization , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Pregnancy , Thalamus/growth & development , Thalamus/metabolismABSTRACT
The insulin-like growth factor-1 (IGF-1) is a pleiotropic factor. Many studies have revealed its importance in the development and maintenance of the central nervous system (CNS). This review will discuss the IGF-1 axis, from the factor itself to the signalling pathways it activates, and its tight regulation. Particular focus will be brought on potential therapeutic targets of the IGF-1 axis in CNS disorders, including brain tumours and neurodegenerative diseases affecting neurons and oligodendrocytes.
Subject(s)
Central Nervous System/physiopathology , Genomic Imprinting , Insulin-Like Growth Factor I/physiology , Nerve Regeneration/immunology , Nerve Regeneration/physiology , Aging/physiology , Animals , Autistic Disorder/immunology , Brain/metabolism , Brain/pathology , Brain Neoplasms/metabolism , Cell Differentiation/physiology , Central Nervous System Diseases/complications , Central Nervous System Diseases/genetics , Central Nervous System Diseases/pathology , Cognition/physiology , Deer , Genetic Therapy , Human Growth Hormone/physiology , Mice , Mice, Knockout , Mice, Transgenic , Neuronal Plasticity/physiology , Oligodendroglia , Signal TransductionABSTRACT
Insulin-like growth factor-1 (IGF-1) interacts with the Type I receptor to activate two main signaling pathways, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-Akt cascades, which mediate proliferation or survival of oligodendrocyte (OL) progenitors (OLPs). In other cellular systems, mammalian target of rapamycin (mTOR) and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E), their regulators (e.g. 4E-binding protein 1, 4E-BP1) and ribosomal protein S6 (S6). The aim of this study was to determine whether these pathways are involved in IGF-1-stimulated protein synthesis, important for growth and differentiation of OLs. Rat cultured OLPs were treated with IGF-1 with or without inhibitors of PI3K (LY294002 or Wortmannin), mTOR (rapamycin), MEK (PD98059), and Akt (III or IV), as well as an adenovirus encoding a dominant negative form of Akt. Protein synthesis, as assessed by [(35)S]-methionine incorporation, was stimulated by IGF-1 and required the upstream activation of PI3K, Akt, mTOR and MEK/ERK. Concordant with the experiments using protein kinase inhibitors, western blotting revealed that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP1. Activation of S6 and inactivation of 4E-BP1, necessary for protein synthesis to take place, were dependent on the upstream activation of PI3K and mTOR. Finally, IGF-1 consistently stimulated protein synthesis through mTOR in differentiating OLPs but mRNA transcription was not required at day 4, indicating a differential role of IGF-1 throughout OL development.
