Figure 1.
Basic intracellular molecular pathways regulating MN survival during development. Cells die through apoptosis (Type I), autophagic cell death (Type II) or necrosis (not pictured). Two different pathways mediate apoptosis, called the intrinsic and extrinsic pathways. The intrinsic pathway involves activation of the pro-apoptotic multi-BH-domain proteins (MDP) Bak and Bax and inhibition of the anti-apoptotic MDPs Bcl-2 and Bcl-XL by the pro-apoptotic BH3-domain-only proteins (BOPs). Bak/Bax activation promote mitochondrial permeability transition (mPT), loss of mitochondrial membrane potential (ψm), release of mitochondrial cytochrome c (cyt c) and activation of caspases (casp3, casp9), which dismantle the cell (lightening strike). Bak/Bax activation also depletes (ψm) by causing the transfer of Ca++ from the endoplasmic reticulum (ER) to the mitochondrion (M). The extrinsic apoptotic pathway directly activates caspases (red arrow) or activates the intrinsic death pathway through the BOP Bid (purple arrow). Autophagic death (lightening strike) occurs independently of apoptosis and is characterized by the presence of abundant autophagic vacuoles (AV) and the activation of autophagic genes (ATGs) such as Beclin 1 (atg6). Cell death is regulated by extracellular anti-apoptotic and pro-apoptotic stimuli that operate through neurotrophic factor receptors (NTFRs) or death receptors (DRs). Activated DRs activate the extrinsic death pathway by assembling a death-inducing signaling complex (DISC). Activated NTFRs antagonize apoptotic, autophagic and necrotic death by activating cytosolic kinases such as phosphoinositide-3 kinase, Akt and B-Raf, inhibiting pro-apoptotic BOP activity, activating anti-apoptotic and inhibiting pro-apoptotic gene expression in the nucleus (N). Blue lines indicate anti-apoptotic function and black lines depict pro-apoptotic function; arrows indicate activation and flat lines indicate inhibition. For details see text.