Neurogenesis, the progression from neural progenitor to committed neuron, is a tightly regulated process, which is fundamental for the development of the central nervous system (CNS) and for the repair of the diseased or injured adult brain. Although many proteins driving neurogenesis are known, the mechanisms coordinating progenitor proliferation and differentiation are not well defined. This knowledge is critical to understand the development of a normal and disordered nervous system and to effectively control the formation of neurons from stem cells. Members of the SoxB family of transcription factors play key roles in neurogenesis and evidence indicates that SoxB1 proteins, which act as transcriptional activators, are required for induction of the CNS and for the maintenance of a proliferating neural progenitor population. In contrast, the closely related SoxB2 proteins function as repressors and are proposed to inhibit soxB1 target genes to control the progression from progenitor to neuron. Although there has been intense study of the function of SoxB1 proteins in different regions of the CNS, much less is known about the SoxB2 subgroup. To better understand the role of SoxB2 transcription factors during vertebrate neurogenesis, we are characterizing the function of the SoxB2 protein, Sox21, in Xenopus laevis. The ease of manipulating the Xenopus embryo will be exploited to test our hypotheses.
In Aim1, using loss of function studies and overexpression of a hormone inducible form of sox21, we test the hypothesis that Sox21 function is dose and context dependent. The function of Sox21 will be examined in the Xenopus neural plate, mid-hindbrain boundary, forebrain and olfactory placode and in the mouse cortex.
With Aim 2, to determine the mechanism of Sox21 function, we will identify partner proteins and target genes through co-immunoprecipitation analysis of candidate protein interactions and expression analysis of candidate target genes, respectively. Completion of the proposed studies will provide substantial insights into the mechanism by which protein level and location affect Sox protein function in general and will specifically elucidate the function and regulation of Sox21 in neurogenesis.
Developing new treatments for brain damage and neurodegenerative diseases requires a better understanding of how stem cell-like properties are regulated in the central nervous system and how progenitor pool expansion and neuronal differentiation are coordinated. While many of the players in these processes are known, their relationships to other proteins in the pathways, their mechanisms of action and direct targets are unknown. This proposal characterizes the function of Sox21, a transcription factor integral to the development of the central nervous system and to the maintenance of a balance of neural progenitors and neurons.
|Whittington, Niteace; Cunningham, Doreen; Le, Thien-Kim et al. (2015) Sox21 regulates the progression of neuronal differentiation in a dose-dependent manner. Dev Biol 397:237-47|