DePew Alison T, Aimino Michael A, Mosca Timothy J
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, United States.
Front Neurosci. 2019 Jan 30;13:27. doi: 10.3389/fnins.2019.00027. eCollection 2019.
To successfully integrate a neuron into a circuit, a myriad of developmental events must occur correctly and in the correct order. Neurons must be born and grow out toward a destination, responding to guidance cues to direct their path. Once arrived, each neuron must segregate to the correct sub-region before sorting through a milieu of incorrect partners to identify the correct partner with which they can connect. Finally, the neuron must make a synaptic connection with their correct partner; a connection that needs to be broadly maintained throughout the life of the animal while remaining responsive to modes of plasticity and pruning. Though many intricate molecular mechanisms have been discovered to regulate each step, recent work showed that a single family of proteins, the Teneurins, regulates a host of these developmental steps in - an example of biological adaptive reuse. Teneurins first influence axon guidance during early development. Once neurons arrive in their target regions, Teneurins enable partner matching and synapse formation in both the central and peripheral nervous systems. Despite these diverse processes and systems, the Teneurins use conserved mechanisms to achieve these goals, as defined by three tenets: (1) transsynaptic interactions with each other, (2) membrane stabilization via an interaction with and regulation of the cytoskeleton, and (3) a role for presynaptic Ten-a in regulating synaptic function. These processes are further distinguished by (1) the nature of the transsynaptic interaction - homophilic interactions (between the same Teneurins) to engage partner matching and heterophilic interactions (between different Teneurins) to enable synaptic connectivity and the proper apposition of pre- and postsynaptic sites and (2) the location of cytoskeletal regulation (presynaptic cytoskeletal regulation in the CNS and postsynaptic regulation of the cytoskeleton at the NMJ). Thus, both the roles and the mechanisms governing them are conserved across processes and synapses. Here, we will highlight the contributions of synaptic biology to our understanding of the Teneurins, discuss the mechanistic conservation that allows the Teneurins to achieve common neurodevelopmental goals, and present new data in support of these points. Finally, we will posit the next steps for understanding how this remarkably versatile family of proteins functions to control multiple distinct events in the creation of a nervous system.
为了成功地将一个神经元整合到一个神经回路中，无数的发育事件必须正确且按正确顺序发生。神经元必须诞生并朝着一个目的地生长，对引导线索做出反应以指引其路径。一旦到达目的地，每个神经元必须在众多不合适的伙伴中进行区分，以找到能够与之建立连接的正确伙伴，然后再分离到正确的子区域。最后，神经元必须与正确的伙伴建立突触连接；这种连接需要在动物的整个生命周期中广泛维持，同时保持对可塑性和修剪模式的响应能力。尽管已经发现了许多复杂的分子机制来调节每个步骤，但最近的研究表明，一类单一的蛋白质——Ten-神经素，在多个发育步骤中发挥调节作用，这是生物适应性重用的一个例子。Ten-神经素在早期发育过程中首先影响轴突导向。一旦神经元到达其目标区域，Ten-神经素在中枢神经系统和外周神经系统中都能促进伙伴匹配和突触形成。尽管存在这些不同的过程和系统，但Ten-神经素通过三个原则所定义的保守机制来实现这些目标：（1）彼此之间的跨突触相互作用；（2）通过与细胞骨架的相互作用和调节来实现膜稳定；（3）突触前的Ten-a在调节突触功能中发挥作用。这些过程的进一步区别在于：（1）跨突触相互作用的性质——同嗜性相互作用（相同的Ten-神经素之间）用于促进伙伴匹配，异嗜性相互作用（不同的Ten-神经素之间）用于实现突触连接以及突触前和突触后位点的正确并置；（2）细胞骨架调节的位置（中枢神经系统中突触前的细胞骨架调节以及神经肌肉接头处突触后的细胞骨架调节）。因此，Ten-神经素的作用及其调控机制在不同过程和突触中都是保守的。在这里，我们将强调突触生物学对我们理解Ten-神经素的贡献，讨论使Ten-神经素能够实现共同神经发育目标的机制保守性，并展示支持这些观点的新数据。最后，我们将提出下一步研究方向，以了解这个极其多功能的蛋白质家族如何在神经系统的形成过程中控制多个不同事件。
