REGULATION OF HETEROCYST DIFFERENTIATION BY HETR/PATA

这项工作使用鱼腥藻7120中的杂胞体形成作为识别和表征基因的模型系统，从而确定生物用来决定细胞命运的分子机制。阐明细胞分化的控制对于理解细胞生长控制的丧失是至关重要的，细胞生长控制的丧失会导致细胞分化状态的扰动，从而导致疾病，如肿瘤细胞生长和人类癌症。鱼腥藻7120的细丝易于培养，世代时间短，可通过遗传操作，并可被诱导形成两种不同细胞类型的可预测模式。最近，已经分离出了几个可以扭曲这种模式的基因。两个基因，特别是hetR和PATA，似乎控制着营养细胞丝状异形胞的分化和模式。过多的hetR拷贝会导致营养细胞向异形胞过度分化，而hetR的缺失则会阻止异形胞的形成。HetR和PATA的分子功能以及它们的生产控制都是未知的。两个新的遗传选择将被用来分离其产物作用于HetR/PATA上游和下游的基因，并将使用生化方法来阐明HetR和PATA之间的功能和关系。通过解剖hetR/PATA调节级联，我们希望阐明一个控制电路，该控制电路将对细菌和多细胞生物体中的细胞分化问题以及由于干扰细胞命运决定的控制而导致的疾病具有指导意义。

The work proposed uses heterocyst formation in Anabaena 7120 as a model system for the identification and characterization of the genes and, consequently, the molecular mechanisms that organisms use to determine cell fate. Elucidation of the controls of cellular differentiation is critical to understanding the loss of cellular growth control that causes a perturbation of the differentiated state of the cell, which can lead to a diseased condition such as neoplastic cell growth and cancer in humans. Filaments of Anabaena 7120 are easily cultured, have a short generation time, are genetically manipulable, and can be induced to form a predictable pattern of two distinct cell types. Recently, several genes have been isolated that can distort this pattern. Two genes in particular, hetR and patA appear to control the differentiation and patterning of heterocysts along a filament of vegetative cells. Extra copies of hetR cause innappropriate excessive differentiation of vegetative cells to heterocysts, whereas lack of hetR prevents heterocyst formation. The molecular functions of HetR and PatA are unknown, as is control of their production. Two novel genetic selections will be used to separately isolate genes whose products act upstream and downstream of HetR/PatA, and biochemical methods will be used to elucidate the functions and the relationship between HetR and PatA. By dissecting the hetR/patA regulatory cascade, we hope to elucidate a control circuit that will be instructive for questions of cellular differentiation in both bacteria and multicellular organisms and the diseases that can result from a disturbance in the control of cell fate determination.