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IntroductionThe four-and-a-half LIM (FHL) proteins are characterized by 4 complete LIM domains preceded by an N-terminal half LIM domain (1). LIM domains are cysteine-rich zinc finger motifs involved in a wide range of protein-protein interactions. Amino acid sequence comparisons reveal that FHL proteins are more than 40% identical.

Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1 , a gene on chromosome 2q31 that encodes α2-chimaerin, a Rac guanosine triphosphatase–activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase α2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance α2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant α2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that α2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

SUMMARY The ocular motility disorder “Congenital fibrosis of the extraocular muscles type 1″ (CFEOM1) results from heterozygous mutations altering the motor and 3rd coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knock-in mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve’s superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a interacting protein and report that Map1b−/− mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1, and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.

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The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities. IntroductionThe association between estrogen and breast cancer was recognized over 100 years ago. Estrogen exerts its function through its 2 nuclear receptors, estrogen receptor α (ERα) and ERβ (1, 2). ER belongs to a superfamily of ligand-activated transcription factors that share structural similarity characterized by several functional domains. N-terminal estrogen-independent and C-terminal estrogen-dependent activation function domains (AF1 and AF2, respectively) contribute to the transcriptional activity of the 2 receptors. The DNAbinding domain of the ERs is centrally located. The ligand-binding domain, overlapping AF2, shows 58% homology between ERα and ERβ. The DNA-binding domain is identical between the 2 receptors, except for 3 amino acids. However, the AF1 domain of ERβ has only 28% homology with that of ERα. The binding of estrogen to ER leads to ER dimerization and its recruitment to the estrogenresponsive elements (EREs) on the promoters of ER target genes, thereby either enhancing or repressing gene activation.The development of breast cancer is associated with dysregulation of ER expression (3-8). Compared with that in normal breast tissues, the proportion of cells expressing ERα is increased, whereas ERβ expression is reduced, in hormone-dependent breast tumors. The ratio of ERα/ERβ expression is higher in breast tumors than in normal tissues, and ERα and ERβ are antagonistic to each other. ERα mediates the tumor-promoting effects of estrogens, whereas ERβ inhibits breast cancer cell growth. ERβ reduces cell proliferation induced by ERα activation. Although ERα and ERβ have been shown to have a yin-yang relationship in breast tumorige...

SUMMARYWe generated a knockout mouse for the neuronalspecific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3−/− mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total b-tubulin levels in Tubb3−/− and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.

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