Summary Human pluripotent stem cells offer promise for use in cell-based therapies for brain injury and diseases. However, their cellular behavior is poorly understood. Here we show that the expression of the brain-specific microRNA-9 (miR-9) is turned on in human neural progenitor cells (hNPCs) derived from human embryonic stem cells. Loss of miR-9 suppressed proliferation but promoted migration of hNPCs cultured in vitro. hNPCs without miR-9 activity also showed enhanced migration when transplanted into mouse embryonic brains or adult brains of a mouse model of stroke. These effects were not due to precocious differentiation of hNPCs. One of the key targets directly regulated by miR-9 encodes stathmin, which increases microtubule instability and whose expression in hNPCs correlates inversely with that of miR-9. Partial inhibition of stathmin activity suppressed the effects of miR-9 loss on proliferation and migration of human or embryonic rat neural progenitors. These results identify miR-9 as a novel regulator that coordinates the proliferation and migration of hNPCs.

WNK1 is a serine-threonine kinase, the expression of which is affected in pseudohypoaldosteronism type II, a Mendelian form of arterial hypertension. We characterized human WNK1 transcripts to determine the molecular mechanisms governing WNK1 expression. We report the presence of two promoters generating two WNK1 isoforms with a complete kinase domain. Further variations are achieved by the use of two polyadenylation sites and tissue-specific splicing. We also determined the structure of a kidney-specific isoform regulated by a third promoter and starting at a novel exon. This transcript is kinase defective and has a predominant expression in the kidney compared to the other WNK1 isoforms, with, furthermore, a highly restricted expression profile in the distal convoluted tubule. We confirmed that the ubiquitous and kidneyspecific promoters are functional in several cells lines and identified core promoters and regulatory elements. In particular, a strong enhancer element upstream from the kidney-specific exon seems specific to renal epithelial cells. Thus, control of human WNK1 gene expression of kinase-active or -deficient isoforms is mediated predominantly through the use of multiple transcription initiation sites and tissue-specific regulatory elements.A new family of serine-threonine kinases was recently described. The members of this family lack a lysine at a usually invariant position in the active site and are therefore known as With No Lysine (WNK) protein kinases (17,20). Rat WNK1 was the first member of this family to be characterized; it has a cysteine in place of the conserved lysine residue in subdomain II of the catalytic domain (20). The active lysine is itself located in subdomain I in both rats and humans. In both species, WNK1 is expressed in a wide variety of tissues, and two major transcripts have been identified. One is produced mainly in heart, muscle, and brain, and the other, shorter transcript is produced mainly in kidney (18,20). The substrates of WNK1 are unknown, but WNK1 is capable of autophosphorylation on serine residues, an activity that is increased in vitro by increasing the salt concentration (20). Like many other protein kinases, WNK1 enzymes contain an autoinhibitory domain outside the catalytic domain, which is capable of abolishing kinase activity in vitro (21). There is also evidence that the autophosphorylation sites detected in the activation loop of WNK1 may control kinase activity (21).Mutations in the genes encoding WNK1 and WNK4, two of the other four members of the human WNK family (17), are responsible for pseudohypoaldosteronism type II (PHA2), also known as Gordon syndrome, an autosomal dominant form of human arterial hypertension associated with hyperkalaemia and metabolic acidosis with hyperchloraemia (5). The mutations in the WNK4 gene are missense mutations clustering in highly conserved domains close to those encoding the coiled-coil domains (18). The location and nature of these mutations suggest that they may result in changes in interactions with as-yet-u...

Mature B cell differentiation involves a well-established transcription factor cascade. However, the temporal dynamics of cell signaling pathways regulating transcription factor network and coordinating cell proliferation and differentiation remain poorly defined. To gain insight into the molecular processes and extrinsic cues required for B cell differentiation, we set up a controlled primary culture system to differentiate human naive B cells into plasma cells (PCs). We identified T cell-produced IL-2 to be critically involved in ERK1/2-triggered PC differentiation. IL-2 drove activated B cell differentiation toward PC independently of its proliferation and survival functions. Indeed, IL-2 potentiated ERK activation and subsequent BACH2 and IRF8 downregulation, sustaining BLIMP1 expression, the master regulator for PC differentiation. Inhibition of the MAPK–ERK pathway, unlike STAT5 signaling, impaired IL-2–induced PC differentiation and rescued the expression profile of BACH2 and IRF8. These results identify IL-2 as a crucial early input in mature B cell fate commitment.