Lopez-Coviella Ignacio, Mellott Tiffany M, Kovacheva Vesela P, Berse Brygida, Slack Barbara E, Zemelko Victoria, Schnitzler Aletta, Blusztajn Jan K
Department of Psychiatry, Boston University School of Medicine, 715 Albany Street, Room L-810, Boston, MA 02118, USA.
Brain Res. 2006 May 9;1088(1):49-56. doi: 10.1016/j.brainres.2006.02.073. Epub 2006 Apr 13.
Basal forebrain cholinergic neurons play critical roles in the organization of brain cortical structures and in processes such as learning and memory. We have previously shown that bone morphogenetic protein (BMP) 9, a member of the transforming growth factor (TGF) beta superfamily of cytokines, is a differentiating factor for cholinergic central nervous system neurons. However, whereas the basic signal transduction pathways for most known members of the TGF-beta superfamily have been well characterized in brain and other organs, nothing is known about the signal transduction pathway of BMP9 in the brain. Here, we describe the pattern of expression of BMP receptors, including Bmpr-Ia, Bmpr-Ib, Bmpr-II, Actr-I. Actr-Ib, Actr-II and Actr-IIb, Alk-1, and Smad proteins (Smads 1-5 and Smad8) in the septal region of the basal forebrain during mouse development. Using cultured basal forebrain cells derived from embryonic day (E) 14 mice, we show that BMP9 causes phosphorylation of Smad1 and Smad5, formation of a complex of Smad4 with Samd1 and/or Smad5, and translocation of these proteins into the nucleus. These data show that BMP9 activates the canonical BMP signaling pathway and suggest that this could be one of the mechanisms responsible for the induction of the cholinergic phenotype by BMP9 in the basal forebrain.
基底前脑胆碱能神经元在大脑皮质结构的组织以及学习和记忆等过程中发挥着关键作用。我们之前已经表明，骨形态发生蛋白（BMP）9是细胞因子转化生长因子（TGF）β超家族的成员之一，是胆碱能中枢神经系统神经元的分化因子。然而，尽管TGF-β超家族的大多数已知成员的基本信号转导途径在大脑和其他器官中已得到充分表征，但关于BMP9在大脑中的信号转导途径却一无所知。在这里，我们描述了小鼠发育过程中基底前脑隔区中BMP受体的表达模式，包括Bmpr-Ia、Bmpr-Ib、Bmpr-II、Actr-I、Actr-Ib、Actr-II和Actr-IIb、Alk-1以及Smad蛋白（Smads 1-5和Smad8）。使用来自胚胎第14天（E14）小鼠的培养基底前脑细胞，我们表明BMP9会导致Smad1和Smad5磷酸化，形成Smad4与Samd1和/或Smad5的复合物，并使这些蛋白质易位到细胞核中。这些数据表明BMP9激活了经典的BMP信号通路，并表明这可能是BMP9在基底前脑诱导胆碱能表型的机制之一。
