Radial glia are highly polarized cells that serve as neuronal progenitors and as scaffolds for neuronal migration during construction of the cerebral cortex. How radial glial cells establish and maintain their morphological polarity is unknown. Using conditional gene targeting in mice, we demonstrate that Adenomatous Polyposis Coli (APC) serves an essential function in the maintenance of polarized radial glial scaffold during brain development. In the absence of APC, radial glial cells lose their polarity and responsiveness to the extracellular polarity maintenance cues, such as neuregulin-1. Elimination of APC further leads to marked instability of the radial glial microtubule cytoskeleton. The resultant changes in radial glial function and loss of APC in radial glial progeny lead to defective generation and migration of cortical neurons, severely disrupted cortical layer formation, and aberrant axonal tract development. Thus APC is an essential regulator of radial glial polarity and is critical for the construction of cerebral cortex in mammals.
Abnormal patterns of head and brain growth are a replicated finding in a subset of individuals with autism spectrum disorder (ASD). It is not known whether risk factors associated with ASD and abnormal brain growth (both overgrowth and undergrowth) converge on common biological pathways and cellular mechanisms in the developing brain. Heterozygous mutations in PTEN (PTEN ϩ/Ϫ ), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are a risk factor for ASD and macrocephaly. Here we use the developing cerebral cortex of Pten ϩ/Ϫ mice to investigate the trajectory of brain overgrowth and underlying cellular mechanisms. We find that overgrowth is detectable from birth to adulthood, is driven by hyperplasia, and coincides with excess neurons at birth and excess glia in adulthood. -Catenin signaling is elevated in the developing Pten ϩ/Ϫ cortex, and a heterozygous mutation in Ctnnb1 (encoding -catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten ϩ/Ϫ cortical overgrowth. Thus, a balance of Pten and -catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth.
Conditional deletion of APC leads to marked disruption of cortical development and to excessive axonal branching of cortical neurons. However, little is known about the cell biological basis of this neuronal morphological regulation. Here we show that APC deficient cortical neuronal growth cones exhibit marked disruption of both microtubule and actin cytoskeleton. Functional analysis of the different APC domains revealed that axonal branches do not result from stabilized β-catenin, and that the C-terminus of APC containing microtubule regulatory domains only partially rescues the branching phenotype. Surprisingly, the N-terminus of APC containing the oligomerization domain and the armadillo repeats completely rescues the branching and cytoskeletal abnormalities. Our data indicate that APC is required for appropriate axon morphological development and that the N-terminus of APC is important for regulation of the neuronal cytoskeleton.
Receptor-interacting protein 3 (RIP3), a member of the RIP Ser/Thr kinase family, has been characterized as a pro-apoptotic protein involved in the tumor necrosis factor receptor-1 signaling pathway. In this study, we have mapped a minimal region of RIP3 sufficient for apoptosis induction to a fragment of 31 amino acids in length. This minimal region also functions as an unconventional nuclear localization signal sufficient to confer the import of full-length RIP3 to the nucleus to trigger apoptosis, suggesting that RIP3 is able to play an apoptosis-inducing role in the nucleus. In addition, we have characterized two novel leucine-rich nuclear export signals (NESs) that are responsible for the nuclear export of RIP3 to the cytoplasm via a chromosome region maintenance 1 (CRM1)-dependent pathway and an extra leucine-rich NES in the N terminus of RIP3 that contributes to the cytoplasmic distribution in a CRM1-independent manner. Thus, we provide the first evidence that RIP3 acts a nucleocytoplasmic shuttling protein, which presents a possible link between death receptor signaling and nuclear apoptosis. The receptor-interacting protein (RIP)1 Ser/Thr kinase family consists of four members, including RIP, RIP2 (RICK/CAR-DIAK), RIP3, and RIP4 (DIK/PKK) (1-4). RIP3 is an important component of the tumor necrosis factor receptor-1 (TNFR1) signaling complex. Sequence analysis reveals that RIP3 contains an N-terminal RIP-like kinase domain (amino acids 21-287) that shares extensive homology with the corresponding N-terminal kinase domain in other RIP family members. Interestingly, in sharp contrast to RIP, which has a C-terminal death domain (DD), RIP2, which has a C-terminal caspaserecruiting domain, and RIP4, which has 11 C-terminal ankyrin repeats, RIP3 possesses a unique C-terminal domain (amino acids 288 -518) that shares no significant homology to any known proteins.It has been shown that the N terminus of RIP3 is required for its kinase activity and autophosphorylation, whereas the C terminus of RIP3 is responsible for caspase activation and apoptosis induction (1-3, 5). Furthermore, RIP3 is recruited to the TNFR1 signaling complex through interaction with RIP via its C-terminal segment, and, once recruited to the complex, RIP3 could exert a pro-apoptotic activity that may be partially accomplished by activating caspases and/or by inhibiting RIPand TNFR1-induced NF-B activation (2, 6). Although RIP3 is involved in TNF-␣-mediated apoptosis, the mechanism by which RIP3 induces cell death remains largely unclear (7). Because the C terminus of RIP3 is unique and involved in apoptosis induction, we are mainly focused on this unique C-terminal segment to investigate its functional significance in RIP3 signaling.Previous studies have demonstrated that both TNF receptorassociated death domain (TRADD) and Fas-associated death domain (FADD), two essential DD-containing adapter molecules, are recruited to the TNFR1 complex during TNF-␣-induced death signaling, and their function and localization are widely assumed to be cyto...
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