Allendoerfer K L, Cabelli R J, Escandón E, Kaplan D R, Nikolics K, Shatz C J
Department of Molecular and Cell Biology, University of California at Berkeley 94720.
J Neurosci. 1994 Mar;14(3 Pt 2):1795-811. doi: 10.1523/JNEUROSCI.14-03-01795.1994.
Cell division, cell death, and remodeling of connections are major features of the construction of the mammalian CNS. We have begun to address the role of neurotrophins in these events through characterization of the expression of their receptors in the developing ferret visual system. By use of chemical cross-linking of iodinated neurotrophins, proteins corresponding to trkB, trkC, and p75 were identified as receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) throughout development. BDNF was also cross-linked to a truncated form of trkB that lacks the tyrosine kinase domain (trkB. T1) in retinal target tissues and in cortex. At the earliest developmental age examined (E24), the ratio of full-length to truncated trkB is > > 1 in the retinal target tissues, LGN and superior colliculus. During the ensuing period of retinal ganglion cell death and segregation into eye-specific layers, the amount of truncated trkB increases markedly relative to full-length trkB. By P27, truncated trkB is the predominant receptor for BDNF in the retinal target tissues and this pattern is maintained into adulthood. Within all subdivisions of visual cortex including the ventricular zone (VZ), intermediate zone (IZ), and cortical plate (CP), similar profiles of bands are observed. The developmental increase in abundance of truncated trkB relative to full-length occurs earliest in the VZ, with a major increase between E30 and P3. In the IZ, this shift to a predominance of truncated trkB occurs between P15 and P30, while in the CP the shift is even further delayed, not occurring until after P30. Within each subdivision of cortex, the shift to a predominance of truncated trkB occurs at times that correlate with the onset of cell death and maturation of axonal connections. This study demonstrates that members of the trk family, previously identified in the CNS on the basis of mRNA transcripts, are present as receptors with specific binding affinities for BDNF and NT-3. Moreover, the correspondence between the developmental shift from full-length to truncated trkB and the critical periods for cell fate determination, cell death, and axonal remodeling suggests an important role for neurotrophic factors in the development of the visual system.
细胞分裂、细胞死亡以及连接重塑是哺乳动物中枢神经系统构建的主要特征。我们已开始通过研究神经营养因子受体在发育中的雪貂视觉系统中的表达，来探讨神经营养因子在这些过程中的作用。通过对碘化神经营养因子进行化学交联，在整个发育过程中，对应于trkB、trkC和p75的蛋白质被鉴定为脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）的受体。在视网膜靶组织和皮质中，BDNF还与一种缺乏酪氨酸激酶结构域的trkB截短形式（trkB.T1）发生交联。在最早检测的发育阶段（E24），视网膜靶组织、外侧膝状体（LGN）和上丘中全长trkB与截短trkB的比例远大于1。在随后的视网膜神经节细胞死亡并分离到眼特异性层的时期，相对于全长trkB，截短trkB的量显著增加。到P27时，截短trkB成为视网膜靶组织中BDNF的主要受体，且这种模式一直维持到成年。在包括脑室区（VZ）、中间区（IZ）和皮质板（CP）在内的视觉皮质的所有亚区中，观察到类似的条带分布。相对于全长trkB，截短trkB丰度的发育性增加最早出现在VZ，在E30和P3之间有显著增加。在IZ，这种向截短trkB占优势的转变发生在P15和P30之间，而在CP中，这种转变甚至更延迟，直到P30之后才发生。在皮质的每个亚区内，向截短trkB占优势的转变发生时间与细胞死亡的开始和轴突连接的成熟相关。这项研究表明，先前基于mRNA转录本在中枢神经系统中鉴定出的trk家族成员，作为对BDNF和NT-3具有特定结合亲和力的受体存在。此外，从全长trkB到截短trkB的发育转变与细胞命运决定、细胞死亡和轴突重塑的关键时期之间的对应关系，表明神经营养因子在视觉系统发育中起重要作用。
