University of Louisville
Ribosomal Biogenesis and Neurite Outgrowth
Institution
University of Louisville
Faculty Advisor/ Mentor
Michal Hetman; Lukasz Somnicki
Abstract
An essential requirement of life is the ability to control growth in response to nutrients. Equally important is a cell’s ability to respond to growth factors released by neighboring cells. Such signal transduction pathways have been extensively studied. Expectedly, the high demand for protein synthesis causes such pathways to upregulate the process of ribosome assembly; up to 50% of the transcriptional output of a non-quiescent cell is dedicated to the transcription of ribosomal RNA (rRNA). Cellular growth signals oftentimes converge on transcription factor 1A (TIF1A), which modulates the activity of RNA polymerase I (Pol-I), the dedicated polymerase of rRNA genes encoding the 5.8S, 18S, and 28S rRNAs. In the developing nervous system, dendrite outgrowth is essential and becomes the largest energy expenditure of neurons. Neuritogenesis is controlled by a class of extracellular factors called neurotrophins, including brain-derived neurotrophic factor (BDNF). It is known that BDNF activates the ERK1/2 signaling cascade which ultimately leads to phosphorylation of TIF1A, stimulating nucleolar transcription and promoting neuritic growth. What has yet to be discovered, however, is how increased Pol-I activity leads to neuritic morphogenesis. To gain insight into this important question, we investigated the involvement of ribosomal biogenesis in the process of BDNF-induced dendrite outgrowth in cultured rat forebrain neurons. We measured the morphogenic response to BDNF or a constitutively active mutant form of TIF1A under conditions of inhibited ribosomal biogenesis with shRNAs targeting ribosomal proteins RPS6, RPS14, and RPL4. We observed that knockdowns of those proteins attenuated neuritic morphogenesis without interfering with nucleolar transcription and/or the structural integrity of the nucleolus. Therefore, making new ribosomes is necessary for neurite outgrowth.
Ribosomal Biogenesis and Neurite Outgrowth
An essential requirement of life is the ability to control growth in response to nutrients. Equally important is a cell’s ability to respond to growth factors released by neighboring cells. Such signal transduction pathways have been extensively studied. Expectedly, the high demand for protein synthesis causes such pathways to upregulate the process of ribosome assembly; up to 50% of the transcriptional output of a non-quiescent cell is dedicated to the transcription of ribosomal RNA (rRNA). Cellular growth signals oftentimes converge on transcription factor 1A (TIF1A), which modulates the activity of RNA polymerase I (Pol-I), the dedicated polymerase of rRNA genes encoding the 5.8S, 18S, and 28S rRNAs. In the developing nervous system, dendrite outgrowth is essential and becomes the largest energy expenditure of neurons. Neuritogenesis is controlled by a class of extracellular factors called neurotrophins, including brain-derived neurotrophic factor (BDNF). It is known that BDNF activates the ERK1/2 signaling cascade which ultimately leads to phosphorylation of TIF1A, stimulating nucleolar transcription and promoting neuritic growth. What has yet to be discovered, however, is how increased Pol-I activity leads to neuritic morphogenesis. To gain insight into this important question, we investigated the involvement of ribosomal biogenesis in the process of BDNF-induced dendrite outgrowth in cultured rat forebrain neurons. We measured the morphogenic response to BDNF or a constitutively active mutant form of TIF1A under conditions of inhibited ribosomal biogenesis with shRNAs targeting ribosomal proteins RPS6, RPS14, and RPL4. We observed that knockdowns of those proteins attenuated neuritic morphogenesis without interfering with nucleolar transcription and/or the structural integrity of the nucleolus. Therefore, making new ribosomes is necessary for neurite outgrowth.