Subunits of mammalian SWI/SNF (mSWI/SNF, also called BAF) complexes have recently been implicated as tumor suppressors in a number of human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of purified endogenous mSWI/SNF complexes. Our studies revealed several new dedicated, stable subunits not found in the yeast SWI/SNF complex including Bcl7a, b and c, Bcl11a and b, Brd9 and SS18. Incorporating these novel members, we determined the frequency of mSWI/SNF subunit mutations in recent exome- and whole-genome sequencing studies of primary human tumors. Surprisingly, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 exome sequencing studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, we find that mutations to more than one subunit, which we define as a type of compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer and that in contrast to other known tumor suppressors and oncogenes surveyed, mSWI/SNF is broadly mutated, similar to TP53. Thus, proper functioning of these polymorphic chromatin regulatory complexes may constitute a major mechanism of human tumor suppression.

Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.

The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of constructs that alter the molecular composition of developing synapses with dual whole-cell electrophysiology to examine synaptic transmission during two distinct developmental stages. We find that SAP102 mediates synaptic trafficking of AMPA and NMDA receptors during synaptogenesis. Surprisingly, after synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for two aspects of synapse maturation: the developmental increase in AMPA receptor transmission and replacement of NR2B-NMDARs with NR2A-NMDARs. In PSD-95/PSD-93 double-KO mice, the maturational replacement of NR2B-with NR2A-NMDARs fails to occur, and PSD-95 expression fully rescues this deficit. This study demonstrates that SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages, thereby playing necessary roles in excitatory synapse development.AMPAR and NMDAR trafficking ͉ membrane-associated guanylate kinase ͉ synaptogenesis ͉ postsynaptic density ͉ synaptic transmission A fundamental goal of developmental neurobiology is to identify the sequence of molecular events underlying excitatory synapse development, a process that can be divided into two distinct stages: synaptogenesis and synapse maturation. Synaptogenesis follows the specification of cell-to-cell contacts mediated by cell adhesion molecules (1, 2) and involves the initiation of chemical communication through the recruitment of pre-and postsynaptic proteins necessary for fast synaptic transmission (3, 4), such as AMPA receptors (AMPARs) and NMDA receptors (NMDARs). Synapse maturation is characterized by two functional events: an increase in the strength of AMPAR-mediated transmission (5, 6) and a switch in the subunit composition of synaptic NMDARs (7). NMDARs are composed of two obligatory NR1 subunits and two NR2 subunits, of which there are four members (NR2A-D) (8). NR2B-NMDARs are expressed during synaptogenesis and are replaced by NR2A-NMDARs during synapse maturation (9-11), a replacement that accounts for the developmental decrease in the NMDAR excitatory postsynaptic current (EPSC) decay time (12, 13) and the loss of sensitivity to the NR2B antagonist ifenprodil (14). The precise molecular mechanisms underlying the differential synaptic trafficking of AMPAR and NMDAR during developmental synaptogenesis and maturation remain largely unknown.PSD-95 is a member of a family of proteins collectively known as membrane-associated guanylate kinases (MAGUKs) (15-17). The PSD-95-like subfamily of neuronal MAGUKs (PSD-MAGUKs) includes PSD-93, SAP102, and SAP97 (15-17). Comparative studies emphasize the remarkable similarities among PSD-MAGUKs in terms of protein-protein interactions (18,19) and overlapping functions in synaptic trafficking of AMPARs at mature synapses (20-24). On the ot...

ALS is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, here we assess the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n=141 exomes). We found that amino acid-altering de novo mutations are enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex component SS18L1/CREST. CREST mutations inhibit activity-dependent neurite outgrowth in primary neurons, and CREST associates with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.