Timing is everything:Prop1,Pou1f1 and the progenitor pool

作者:CAMPER Sally A;DAVIS Shannon W 刊名: 上传者:陈华芳

【摘要】A cadre of transcription factors regulates normal pituitary development and function in mouse and man. Expression of these genes is activated stepwise over the course of mouse development and early neonatal life,with some genes exhibiting dynamic expression patterns that are essentially fetal-specific,while others yield constitutive expression into adulthood.The timing of gene expression in normal mice and the alterations caused by mouse mutations have revealed a genetic hierarchy of transcriptional control,with some transcription factors playing important roles in several developmental stages.Lesions in the earliest acting genes cause defects in pituitary gland and head development,while genes acting later in pituitary development,like Propl and Poulfl,tend to produce non-syndromic pituitary hormone deficiency.Mutations in Propl and Poulfl cause similar pituitary hormone deficits, yet there is a substantial temporal lag between peak Propl and Poulfl expression,and only Propl mutant mice exhibit profound pituitary dysmorphology.The spatial and temporal expression of Propl is consistent with a role in regulating the transition from proliferating to differentiating cells.Birth dating studies reveal that most differentiated pituitary cells present in late gestation emerge from the proliferative compartment near the time of peak Propl expression.In the absence of Propl,the progenitor cells fail to migrate to form the anterior lobe,and poor vascularization and enhanced apoptosis are evident.These features contrast with those of Poulfl mutants,which include normal vascularization,and pituitaries that are indistinguishable in size and morphology from those of their normal littermates at birth.These differences support the idea that Propl controls the expression of genes that are important for migration,survival,and differentiation of pituitary cells.These genes are candidates for cases of human hormone deficiencies of unknown etiology.We took several approaches to identify such genes,including construction of full-length cDNA libraries and microarray analysis of gene expression.The cDNA libraries from Propl mutant and normal embryonic pituitaries contain over 40000 sequences in a searchable database.Bioinformatics analysis of this collection and comparison of pituitary transcripts from newborn Propl and Poulfl mutants and their littermates revealed a collection of novel transcription factors and several processes that are significantly different in Propl mutants,namely Wnt-frizzled signaling,organ morphogenesis,and anterior-posterior patterning. Because genes discovered in the mouse have led quickly to the discovery of lesions in human patients,we anticipate that these approaches will reveal genes that regulate pituitary development and underlie some cases of human pituitary hormone deficiency disease.

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