Investigation into the mechanisms for generating interneuron diversity

描述（申请人提供）：gaba能中间神经元是神经系统中抑制的主要来源，在每个脑回路中起关键作用。皮层中间神经元的异常发育和功能与许多神经系统疾病如精神分裂症、自闭症和癫痫的病理生物学有关。由于这些疾病的发病早于成年期，因此需要更好地了解正常发育和疾病模型中的中间神经元分化和成熟。这个K99/R00应用程序将支持Timothy Petros博士在他的追求发展创新的策略和获得新的技能，以研究中间神经元的发展。实验将在受指导期间开始（在纽约大学的Gord Fishell博士的实验室进行），并在获得独立职位后继续在Petros博士自己的实验室进行。彼得斯博士的长期职业目标是揭示直接决定中间神经元命运和成熟的机制，希望为治疗各种神经系统疾病开发新的治疗靶点。Petros博士之前的工作已经确定了一种新机制，可以调节来自内侧神经节凸起（MGE）的最大的、与临床相关的中间神经元群体的命运决定：通过间接神经发生，表达小蛋白（PV+）的细胞优先从中间神经元祖细胞（INPs）中产生，而直接神经发生主要产生表达生长抑素（Sst+）的中间神经元。调控这一决定的分子机制尚不清楚，但我们的初步数据表明，Jagged1和notch信号可能参与这一过程。Specific Aim 1将使用多重输入

DESCRIPTION (provided by applicant): GABAergic interneurons are the primary source of inhibition in the nervous system and play critical roles in every brain circuit. The abnormal development and function of cortical interneurons has been implicated in the pathobiology of many neurological disorders such as schizophrenia, autism, and epilepsy. As the onset of these diseases presents prior to adulthood, a better understanding of interneuron differentiation and maturation in normal development and disease models is required. This K99/R00 application will support Dr. Timothy Petros in his pursuit of developing innovative strategies and acquiring new skill sets to study interneuron development. The experiments will be initiated during the mentored period (carried out in Dr. Gord Fishell's lab at NYU) and continue in Dr. Petros' own laboratory upon securing an independent position. Dr. Petros' long-term career goal is to unravel the mechanisms that direct interneuron fate determination and maturation, with the hope of developing new therapeutic targets for treating a variety of neurological diseases. Dr. Petros' previous work has identified a novel mechanism regulating fate decisions for the largest, clinically- relevant interneuron populations arising from the medial ganglionic eminence (MGE): parvalbumin-expressing (PV+) cells preferentially arise from intermediate neuronal progenitors (INPs) via indirect neurogenesis whereas direct neurogenesis primarily gives rise to somatostatin-expressing (Sst+) interneurons. The molecular mechanisms that regulate this decision remain unknown, but out preliminary data demonstrate a strong potential for involvement of Jagged1 and notch signaling in this process. Specific Aim 1 will utilize multiple in vitro and in vivo approaches to investigate the hypothesis that Jagged1 inhibits notch activity in the MGE to promote direct neurogenesis and formation of Sst+ cells. The MGE is a heterogeneous population of progenitors that gives rise to many different cell types, and since somatostatin and parvalbumin are not expressed in the MGE, we currently lack cell markers and genetic strategies to distinguish these cells. Ideally, we would like to determine the transcriptional profile of a cell undergoing fate decisions in the MGE while at the same time retain the ability to identify which type of interneuron (PV+ or Sst+) it becomes in the postnatal brain. To this end, Specific Aim 2 will create a spatially restricted and temporally inducible form of Dam-identification (DamID) to 'time-stamp' the transcriptome of MGE progenitors for future analysis. Initial experiments will utilize ESC technology that will lead to generation of new mouse strains to identify novel fate-determining genes in Sst+ and PV+ interneurons. Importantly, the proposed experiments should significantly advance our understanding of interneuron development and pave the way for Dr. Petros to secure an independent position in academia.