Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2011; 108(18):7607-12. DOI: 10.1073/pnas.1101347108
Source: PubMed


The organization of neural progenitors in the developing mammalian neuroepithelium is marked by cadherin-based adherens junctions. Whereas RhoA, a founding member of the small Rho GTPase family, has been shown to play important roles in epithelial adherens junctions, its physiological roles in neural development remain uncertain due to the lack of specific loss-of-function studies. Here, we show that RhoA protein accumulates at adherens junctions in the developing mouse brain and colocalizes to the cadherin-catenin complex. Conditional deletion of RhoA in midbrain and forebrain neural progenitors using Wnt1-Cre and Foxg1-Cre mice, respectively, disrupts apical adherens junctions and causes massive dysplasia of the brain. Furthermore, RhoA-deficient neural progenitor cells exhibit accelerated proliferation, reduction of cell- cycle exit, and increased expression of downstream target genes of the hedgehog pathway. Consequently, both lines of conditional RhoA-deficient embryos exhibit expansion of neural progenitor cells and exencephaly-like protrusions. These results demonstrate a critical role of RhoA in the maintenance of apical adherens junctions and the regulation of neural progenitor proliferation in the developing mammalian brain.

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    • "RESEARCH ARTICLE Development (2014) 141, 4076-4086 doi:10.1242/dev.108282 DEVELOPMENT Katayama et al., 2011; Komada et al., 2008). mTOR-deficient progenitors show a failure of cell cycle re-entry. "
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    ABSTRACT: Balanced control of neural progenitor maintenance and neuron production is crucial in establishing functional neural circuits during brain development, and abnormalities in this process are implicated in many neurological diseases. However, the regulatory mechanisms of neural progenitor homeostasis remain poorly understood. Here, we show that mammalian target of rapamycin (mTOR) is required for maintaining neural progenitor pools and plays a key role in mediating glycogen synthase kinase 3 (GSK3) signaling during brain development. First, we generated and characterized conditional mutant mice exhibiting deletion of mTOR in neural progenitors and neurons in the developing brain using Nestin-cre and Nex-cre lines, respectively. The elimination of mTOR resulted in abnormal cell cycle progression of neural progenitors in the developing brain and thereby disruption of progenitor self-renewal. Accordingly, production of intermediate progenitors and postmitotic neurons were markedly suppressed. Next, we discovered that GSK3, a master regulator of neural progenitors, interacts with mTOR and controls its activity in cortical progenitors. Finally, we found that inactivation of mTOR activity suppresses the abnormal proliferation of neural progenitors induced by GSK3 deletion. Our findings reveal that the interaction between mTOR and GSK3 signaling plays an essential role in dynamic homeostasis of neural progenitors during brain development.
    Development 10/2014; 141(21). DOI:10.1242/dev.108282 · 6.46 Impact Factor
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    • "For other genes, we used EST clones (Invitrogen) to produce probes [14]. Nissl staining was also performed as described previously [18], [19]. To reveal the general innervation patterns of the inner ear, nerve fibers were visualized with the lipophilic tracer, DiI (Invitrogen). "
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    ABSTRACT: Statoacoustic ganglion (SAG) neurons project sensory afferents to appropriate targets in the inner ear to form functional vestibular and auditory circuits. Neuropilin1 (Npn1), a receptor for class 3 semaphorins, is required to generate appropriate afferent projections in SAG neurons; however, the ligands and coreceptors involved in Npn1 functioning remain unknown. Here we show that both plexinA1 and plexinA3 are expressed by SAG neurons, and plexinA1/plexinA3 double mutant mice show defects in afferent projections of SAG neurons in the inner ear. In control mice, sensory afferents of SAG neurons terminate at the vestibular sensory patches, whereas in plexinA1/plexinA3 double mutants, they extend more dorsally in the inner ear beyond normal vestibular target areas. Moreover, we find that semaphorin3a (Sema3a) is expressed in the dorsal otocyst, and Sema3a mutant mice show defects in afferent projections of SAG neurons similar to those observed in plexinA1/plexinA3 double mutants and in mice lacking a functional Npn1 receptor. Taken together, these genetic findings demonstrate that Sema3a repellent signaling plays a role in the establishment of proper afferent projections in SAG neurons, and this signaling likely occurs through a receptor complex involving Npn1 and either plexinA1 or plexinA3.
    PLoS ONE 08/2013; 8(8):e72512. DOI:10.1371/journal.pone.0072512 · 3.23 Impact Factor
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    • "The Wnt1-Cre mouse transgenic line is widely used for interrogating gene function and cell lineage relationships in a variety of developmental contexts including early neural crest migration, secondary palate, calvaria, cardiac outflow tract, and midbrain development (Brewer et al., 2004; Chai et al., 2000; Ito et al., 2003; Jiang et al., 2000, 2002; Katayama et al., 2011; Merrill et al., 2006; Tallquist and Soriano, 2003; Yoshida et al., 2008). Its utility is based on the fact that the Wnt1 gene is highly expressed in the dorsal neural tube prior to the emigration of the neural crest and in the midbrain–hindbrain boundary (MHB) at the initiation of midbrain development. "
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    ABSTRACT: The Wnt1-Cre transgenic mouse line is extensively used in the study of the development of the neural crest and its derivatives and the midbrain. The Wnt1 gene has important developmental roles in formation of the midbrain-hindbrain boundary, regulation of midbrain size, and neurogenesis of ventral midbrain dopaminergic (mDA) neurons. Here, we report that Wnt1-Cre transgenic mice exhibit phenotypes in multiple aspects of midbrain development. Significant expansion of the midbrain and increased proliferation in the developing inferior colliculus is associated with ectopic expression of Wnt1. Marked elevation of Wnt1 expression in the ventral midbrain is correlated with disruption of the differentiation program of ventral mDA neurons. We find that these phenotypes can be attributed to ectopic expression of Wnt1 from the Wnt1-Cre transgene leading to the ectopic activation of canonical Wnt/β-catenin signaling. Since these caveats could complicate the utility of Wnt1-Cre in some developmental circumstances, we report a new Wnt1-Cre2 transgenic mouse line that can serve the same purposes as the original without the associated phenotypic complications. These studies reveal an important caveat to a widely-used reagent, provide an improved version of this reagent, and indicate that the original Wnt1-Cre transgenic mouse line may be useful as a gain of function model for interrogating Wnt signaling mechanisms in multiple aspects of midbrain development.
    Developmental Biology 05/2013; 379(2). DOI:10.1016/j.ydbio.2013.04.026 · 3.55 Impact Factor
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