Brian Howell博士

研究抽象

Brain development is an exquisitely regulated phenomenon, whereby waves of differentiation produce diverse classes of neurons, 少突胶质细胞，最后, 星形胶质细胞. 最终这些细胞, 尤其是神经元, organize into functional networks that receive, 整合和传递信息. My lab studies how molecular signaling regulates the migration of neurons from their site of origin to destinations where they extend processes, form synapses 和 integrate into networks. One of our focuses is to investigate how the Reelin signaling pathway influences the positioning of distinct neuronal classes into stereotypical layers in the brain. Reelin, 分泌的配体, induces the tyrosine phosphorylation of the intra细胞ular docking protein Dab1 by clustering the neuronal receptors ApoER2 和 VLDLR 和 activating Src-family kinases. 的 tyrosine phosphorylation of Dab1 generates signaling complexes that includes the molecules Nckβ, Crk, CrkL和PI3K. 的se complexes regulate the behavior of neurons as they migrate, 使它们能够分层. We have shown that Reelin signaling influences the extension of the Golgi apparatus into neuronal dendrites 和 the ability of neurons to polarize. We are currently investigating how these 细胞ular behaviors influence neuronal positioning 和 other neuronal properties regulated by Reelin signaling.

图1. Reln is required for proper Golgi elongation 和 orientation in the hippocampus at birth. Hippocampal neurons identified by Ctip2 immunostaining typically have elongated GRASP65-positive Golgi that extend into the apical dendrite. 相反，在纯合子中 Reln mutant animals the Golgi apparatus is convoluted proximal to the nucleus.

图2. Stk25, a genetic modifier of the phospho Tau phenotype in Dab1 mutant mice, influences neuronal migration. 与本构相反 Stk25 knockout, the acute inactivation of a conditional allele of Stk25 绿色荧光蛋白-Cre在E14的表达.5 causes aberrant neuronal migration apparent by E17.5.

图3. 击倒的 Stk25 导致树突发生异常. Expression of an Stk25 shRNA in the hippocampus at E16.5 results in reduced dendritic asymmetry between the apical 和 basal dendrites.

We have recently exp和ed our focus to include genetic causes of autism spectrum disorder (ASD); specifically RELN mutations, more than 40 of which have been identified in ASD patients. We have found that mutations are enriched in an Arg-X-Arg motif in the core of the Reelin subrepeat domains. 的 function of the paired Arg residues is unknown. 因此, we are working to resolve the consequences of mutations in this motif in Reelin biosynthesis 和 signaling with the ultimate goal of determining how they contribute to ASD.

选定的出版物

Sutt年代, Cansby E, 保罗一, Amrutkar米, 努涅斯·杜兰E, Kulkarni纳米, 斯塔尔米, 博伦J, Laurencikiene J, 豪厄尔BW， Enerbäck S, Mahlapuu M. STK25 regulates oxidative capacity 和 metabolic efficiency in adipose tissue. J性. 2018年5月24日. pii:乔- 18 - 0182. doi: 10.1530 /乔- 18 - 0182. [Epub预印]PMID:29794231

拉默特,维.B.米德尔顿，F.A.潘，J.奥尔森，E.C. 和 豪厄尔,B.W. (2017) 的 新创 自闭症谱系障碍 RELN R2290C Mutation Reduces Reelin Secretion 和 Increases Protein Disulfide Isomerase Expression. J Neurochem. 142:89-102. doi: 10.1111 / jnc.14045

拉默特DB, 豪厄尔BW. RELN Mutations in 自闭症谱系障碍. 前细胞神经科学. 2016年3月31日;10:84. doi: 10.3389 / fncel.2016.00084. eCollection 2016. 审查.PMID: 27064498

Abadesco AD, Cilluffo M, Yvone GM, Carpenter EM, 豪厄尔BW菲尔普斯体育. Novel Disabled-1-expressing neurons identified in adult brain 和 spinal cord. 【推荐最近最火的赌博软件】. 2014年2月,39 (4):579 - 92. doi: 10.1111 / ejn.12416. 2013年11月19日.PMID: 24251407

Matsuki T, Chen J， 豪厄尔BW. Acute inactivation of the serine-threonine kinase Stk25 disrupts neuronal migration. 神经系统开发. 2013年11月13日;8:21. doi: 10.1186/1749-8104-8-21.PMID: 24225308

特谢拉厘米, 克隆亚麻毫米, Masachs N, 张H, Lagace直流, 马丁内斯一, Reillo我, 段X, 博世C, Pujadas L, Brunso L, 歌H, Eisch AJ, 博雷利V, 豪厄尔BW，家长JM，索里亚诺E. 细胞-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus. J >. 2012年8月29日;32(35):12051-65.PMID: 22933789

Matsuki T, Zaka M, Guerreiro R, van der Brug MP, Cooper JA, Cookson MR, Hardy JA, 豪厄尔BW. Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice. 《推荐最近最火的赌博软件》. 2012;7(2):e31152. doi: 10.1371 /杂志.玉米饼.0031152. 2012年2月15日.PMID: 22355340

Matsuki T, Matthews RT, Cooper JA, van der Brug MP, Cookson MR, Hardy JA, Olson EC, 豪厄尔BW. Reelin 和 stk25 have opposing roles in neuronal polarization 和 dendritic Golgi deployment. 细胞. 2010年11月24日;143(5):826-36. doi: 10.1016/j.细胞.2010.10.029.PMID: 21111240

Matsuki T, Pramatarova A， 豪厄尔BW. Reduction of Crk 和 CrkL expression blocks reelin-induced dendritogenesis. [J]细胞科学. 2008年6月1日;121(11):1869-75. doi: 10.1242 / jcs.027334. 2008年5月13日.PMID: 18477607

Pramatarova A, Chen K， 豪厄尔BW. A genetic interaction between the APP 和 Dab1 genes influences brain development. Mol细胞神经科学. 2008年1月,37 (1):178 - 86. Epub 2007 9月26日.PMID: 18029196

Pramatarova A, Ochalski PG, Lee CH， 豪厄尔BW. Mouse disabled 1 regulates the nuclear position of neurons in a Drosophila eye model. Mol细胞生物学. 2006年2月,26 (4):1510 - 7.PMID: 16449660

豪厄尔,B.W.赫里克，T.M.希尔德布兰德，J.D.张，Y.库珀，J.A. (2000).  Dab1 tyrosine  phosphorylation  sites  relay  positional signals  during  mouse brain  development. 现代生物学10:877-885. PMID: 10959835

豪厄尔,B.W.赫里克，T.库珀，J.A. (1999) Reelin-induced tyrosine phosphorylation of Disabled 1 during neuronal positioning. 基因开发.13 (6):643-648

豪厄尔,B.W.霍克斯，R.索里亚诺，P.库珀，J.A. (1997). Neuronal position in the developing brain is regulated by mouse disabled. 自然科学学报，39 (3):733-737.