Molecular Mechanisms that Initiate Apical Dendrite Development During Embryonic Neuronal Development

启动先导过程和顶端枝晶极化的分子机制 在胚胎神经元发育过程中 哺乳动物胚胎脑发育的早期和基本事件是神经元极化，其中不同的 轴突和树突室形成。轴突和树突在分子组成上有本质的不同。 它们的细胞质、细胞骨架和质膜。这些差异奠定了独特的形态和 这些隔间的功能，负责大脑中定向的信息流。神经元中的像差 极化导致发育神经病变、智力残疾、癫痫、自闭症谱系障碍，以及 神经精神病理学。有丝分裂后新皮质和海马CA1区双极的建立 锥体神经元前体标记轴突和顶端树突的极化。顶端的树突将 从双极神经元的前导过程发展而来，而拖尾过程将成为轴突。 轴突的规范主导了对神经元极化的研究，从而产生了对 轴突同一性、具体化和生长的潜在机制。许多努力也都指向了 阐明控制树突形态发生的后期事件的机制--生长、分枝和结构 可塑性。然而，导致双极极化和随后的顶端树枝晶发展的事件， 仍然难以捉摸。我们提出了通过局部组装产生明显更高的环状GMP(CGMP) CGMP产生机制位于发育中的锥体神经元的前沿，促进两极极化， 主导工艺形成和顶端枝晶发育。使用最先进的寿命衰减片 急性脑片结合前沿遗传学对发育中的锥体神经元cGMP的测定 CGMP生产的操作和局部的、定向的光遗传操作，这项研究旨在 确定cGMP在极性建立和顶端树突发育过程中的时空调节， 明确其体内发育锥体神经元的机制基础。我们的研究将为我们提供重要的 轴突和顶端树突发生的早期分子事件研究进展 在啮齿类动物脑内主要兴奋性神经元的建立，并将有助于识别 异常所致发育神经病理的分子靶点及治疗进展 轴突和树突的发育。

Molecular mechanisms that initiate leading process and apical dendrite polarization during embryonic neuronal development An early and essential event in mammalian embryonic brain development is neuronal polarization, in which distinct axonal and dendritic compartments are formed. Axons and dendrites inherently differ in the molecular composition of their cytoplasm, cytoskeleton, and plasma membrane. These differences underlie the unique morphology and function of these compartments, and are responsible for directed information flow in the brain. Aberrations in neuron polarization lead to developmental neuropathologies, intellectual disability, epilepsy, autism spectrum disorders, and neuropsychiatric pathologies. Bipolar polarity establishment in postmitotic neocortical and hippocampal CA1 pyramidal neuron progenitors marks polarization of the axon and the apical dendrite. The apical dendrite will develop from the leading process of the bipolar neuron whereas the trailing process will become the axon. Specification of the axon has dominated studies on neuron polarization, yielding an understanding of the mechanisms underlying axonal identity, its specification and growth. Much effort has also been directed towards elucidation of the mechanisms that control later events in dendrite morphogenesis - growth, branching, and structural plasticity. However, the events leading to bipolar polarity and the subsequent development of the apical dendrite, have remained elusive. We propose that distinctly higher cyclic GMP (cGMP) generated via localized assembly of a cGMP production machinery at the leading edge of developing pyramidal neurons, promotes bipolar polarity, leading process formation, and apical dendrite development. Using state of the art lifetime decay FLIM-FRET cGMP measurements in mouse developing pyramidal neurons in acute slice, combined with cutting edge genetic manipulations, and localized, directed optogenetic manipulations of cGMP production, this study is designed to determine the spatio-temporal regulation of cGMP during polarity establishment and apical dendrite development, and to identify its mechanistic basis in developing pyramidal neurons in vivo. Our studies will provide important advance in the understanding of the early molecular events that take place during axon and apical dendrite establishment in principal excitatory neurons in the rodent brain, and will contribute to the identification of molecular targets and development of therapeutics for developmental neuropathologies resulting from abnormal axon and dendrite development.