MeCP2 functions largely cell-autonomously, but also non-cell-autonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons.

نویسندگان

  • Noriyuki Kishi
  • Jeffrey D Macklis
چکیده

Rett syndrome is a human neurodevelopmental disorder presenting almost exclusively in female infants; it is the second most common cause of mental retardation in girls, after Down's syndrome. The identification in 1999 that mutation of the methyl-CpG-binding protein 2 (MECP2) gene on the X chromosome causes Rett syndrome has led to a rapid increase in understanding of the neurobiological basis of the disorder. However, much about the functional role of MeCP2, and the cellular phenotype of both patients with Rett syndrome and mutant Mecp2 mouse models, remains unclear. Building on prior work in which we demonstrated that cortical layer 2/3 pyramidal neurons (primarily interhemispheric "callosal projection neurons" (CPN)) have reduced dendritic complexity and smaller somata in Mecp2-null mice, here we investigate whether Mecp2 loss-of-function affects neuronal maturation cell-autonomously and/or non-cell-autonomously by creating physical chimeras. We transplanted Mecp2-null or wild-type (wt) E17-18 cortical neuroblasts and immature neurons from mice constitutively expressing enhanced green fluorescent protein (eGFP) into wt P2-3 mouse cortices to generate chimeric cortices. Mecp2-null layer 2/3 pyramidal neurons in both Mecp2-null and wt neonatal cortices exhibit equivalent reduction in dendritic complexity, and are smaller than transplanted wt neurons, independent of recipient environment. These results indicate that the phenotype of Mecp2-null pyramidal neurons results largely from cell-autonomous mechanisms, with additional non-cell-autonomous effects. Dysregulation of MeCP2 target genes in individual neuronal populations such as CPN is likely centrally involved in Rett syndrome pathogenesis. Our results indicating MeCP2 function in the centrally affected projection neuron population of CPN themselves provide a foundation and motivation for identification of transcriptionally regulated MeCP2 target genes in developing CPN.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

disabled-1 functions cell autonomously during radial migration and cortical layering of pyramidal neurons.

Genetic mosaics offer an excellent opportunity to analyze complex gene functions. Chimeras consisting of mutant and wild-type cells provide not only the avenue for lineage-specific gene rescue but can also distinguish cell-autonomous from non-cell-autonomous gene functions. Using an independent genetic marker for wild-type cells, we constructed Dab1(+/+) <--> Dab1(-/-) chimeras with the aim of ...

متن کامل

MeCP2 Mutation Results in Compartment-Specific Reductions in Dendritic Branching and Spine Density in Layer 5 Motor Cortical Neurons of YFP-H Mice

Rett Syndrome (RTT) is a neurodevelopmental disorder predominantly caused by mutations in the X-linked gene MECP2. A primary feature of the syndrome is the impaired maturation and maintenance of excitatory synapses in the central nervous system (CNS). Different RTT mouse models have shown that particular Mecp2 mutations have highly variable effects on neuronal architecture. Distinguishing MeCP2...

متن کامل

Wiring Economy of Pyramidal Cells in the Juvenile Rat Somatosensory Cortex

Ever since Cajal hypothesized that the structure of neurons is designed in such a way as to save space, time and matter, numerous researchers have analyzed wiring properties at different scales of brain organization. Here we test the hypothesis that individual pyramidal cells, the most abundant type of neuron in the cerebral cortex, optimize brain connectivity in terms of wiring length. In this...

متن کامل

MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions.

Rett syndrome is a neurodevelopmental disorder and one of the causes of mental retardation and autistic behavior in girls, as well as in a small group of boys. It was recently discovered that mutation of the methyl-CpG-binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome causes Rett syndrome. Although it is evident that phenotypes of MECP2 mutant mice that res...

متن کامل

(S)- 3,5-Dihydroxyphenylglycine )an agonist for group I metabotropic glutamate receptors( induced synaptic potentiation at excitatory synapses on fast spiking GABAergic cells in visual cortex

Introduction: (S)- 3,5-Dihydroxyphenylglycine (DHPG) is an agonist for group I metabotropic glutamate receptors. DHPG-induced synaptic depression of excitatory synapses on hippocampal pyramidal neurons is well known model for synaptic plasticity studies. The aim of the present study was to examine the effects of DHPG superfusion on excitatory synapses on pyramidal and fast-spiking GABAergic cel...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Experimental neurology

دوره 222 1  شماره 

صفحات  -

تاریخ انتشار 2010