Studies On Key Developmental Regulatory Mechanisms Associated With Dopaminergic Neuron During Degeneration And Regeneration

Abstract

Dopamine (DA) is involved in many functions viz., reward, motivation, memory, attention and even regulating body movements. In the mammalian central nervous system (CNS), mesencephalic dopaminergic (mDA) neurons are the main source of dopamine. The development of mDA neurons involves complex events from proliferation, and differentiation of neuron progenitors; and maturation to form mDA neurons. Multiple signaling pathways and specific Transcription Factors (TF s) guide these events at each differentiation stage which is used as the foundation for driving mDA neuron differentiation and maturation. In addition to these transcription factors, microRNAs and mitochondria have been identified as critical players to confer mDA identity. The cascade of transcriptional and posttranscriptional regulation form a gene network to maintain the mitochondrial function that confers mDA identity by maintaining the motor functions and regulates their functions. Although loss of midbrain dopaminergic neurons is associated with one of the most common human neurological disorders, Parkinson s disease. This disease is clinically characterized by motor symptoms like bradykinesia, tremor and akinesia; but also, impairment of cognitive capabilities. However, these symptoms manifest only after 70-80% of mDA neurons have been degenerated. This is devastating because the adult CNS has extremely limited intrinsic regeneration to replace the lost neurons. Unfortunately, the loss of DA neurons cannot be rescued or reversed by drug administration. Unraveling the mechanisms of midbrain dopaminergic (mDA) phenotype induction and maturation and elucidating the role of the gene network involved in the newline newline newline newline newline newlinedevelopment and maintenance of these neurons is of pivotal importance to rescue or substitute these cells in order to restore dopaminergic functions. newline newlineIn contrast to mammals, the developmental period of the dopaminergic system in zebrafish (18 96Hpf) (Hours post-fertilization) is homologous to those in humans. The earliest differentiation of DA