| Popis: |
The embryonic telencephalon is one of the most intricate regions of the mammalian brain and gives rise to a diverse array of neurons and glial cells functioning in motor coordination, higher cognition, consciousness and emotions. As a sub-domain of the ventral telencephalon, the lateral ganglionic eminence (LGE) is known to generate two major neuronal subtypes of important biological significance, olfactory bulb interneurons which exhibit continuous regeneration throughout the adult lifetime and striatal projection neurons which become vulnerable and dysfunctional in Huntington’s disease. The aim of this thesis study is to elucidate the transcriptional control of specification and differentiation of LGE neuronal subtypes. Understanding the molecular mechanism underlying the generation of particular neuronal fates will improve the prospect of developing stem cell-based cell replacement therapy for nervous system repair. Gsx2, a murine homeobox gene, is expressed in the LGE germinal zone and is required for the correct molecular specification of LGE progenitors. Using a temporally regulated gain-of-function approach, Gsx2 was shown to specify striatal projection neurons and olfactory bulb interneurons at distinct time points during telencephalic neurogenesis. Gsx1 is a homebox gene closely related to Gsx2 and has been shown to compensate, at least in part, for the loss of Gsx2 in the specification of LGE progenitors. However, the fact that Gsx1 mutants exhibit no obvious telencephalic defects has made it difficult to determine the role(s) of Gsx1 in development of the ventral telencephalon. Using a gain-of-function approach to express Gsx1 throughout the telencephalon, similar to that for Gsx2, revealed that Gsx1 functions similarly to Gsx2 in the specification of LGE identity. Interestingly, however, Gsx1 and Gsx2 were shown to function differently in the regulation of the proliferation and maturation of telencephalic progenitors. Downstream of Gsx1 and Gsx2, Ascl1 and Dlx1/2 are known transcription factors involved in development of the ventral telencephalon. Utilizing the same gain-of-function approach combined with loss-of-function mutations of either Ascl1 or Dlx12 demonstrated that Gsx genes specify LGE neuronal subtypes via the sequential activation of Ascl1 and Dlx1/2, which in turn promote the expression of further downstream factors Islet-1 and Sp8. These latter factors are involved in the specification of striatal and olfactory bulb neuronal fates, respectively. |
