Early Control of Mycobacterium tuberculosis Infection Requiresil12rb1Expression byrag1-Dependent Lineages

ABSTRACTIL12RB1is essential for human resistance toMycobacterium tuberculosisinfection. In the absence of a functionalIL12RB1allele, individuals exhibit susceptibility to disseminated, recurrent mycobacterial infections that are associated with defects in bothRAG1-dependent andRAG1-independent hematopoietic lineages. Despite this well-established association, a causal relationship betweenM. tuberculosissusceptibility andIL12RB1deficiency in eitherRAG1-dependent orRAG1-independent lineages has never been formally tested. Here, we use the low-dose aerosol model of experimental tuberculosis (TB) to both establish that infectedil12rb1−/−mice recapitulate important aspects of TB inIL12RB1null individuals and, more importantly, use radiation bone marrow chimeras to demonstrate that restriction ofil12rb1deficiency solely torag1-dependent lineages (i.e., T and B cells) allows for the full transfer of theil12rb1−/−phenotype. We further demonstrate that the protection afforded by adaptive lymphocyteil12rb1expression is mediated partially throughifngand that, within the same infection,il12rb1-sufficient T cells exhibit dominance overil12rb1-deficient T cells by enhancingifngexpression in the latter population. Collectively, our data establish a basic framework in which to understand howIL12RB1promotes control of this significant human disease.

Comparison of the generic neuronal differentiation and neuron subtype specification functions of mammalian achaete-scute and atonal homologs in cultured neural progenitor cells

In the vertebrate peripheral nervous system, the proneural genes neurogenin 1 and neurogenin 2 (Ngn1 and Ngn2), and Mash1 are required for sensory and autonomic neurogenesis, respectively. In cultures of neural tube-derived, primitive PNS progenitors NGNs promote expression of sensory markers and MASH1 that of autonomic markers. These effects do not simply reflect enhanced neuronal differentiation, suggesting that both bHLH factors also specify neuronal identity like their Drosophila counterparts. At high concentrations of BMP2 or in neural crest stem cells (NCSCs), however, NGNs like MASH1 promote only autonomic marker expression. These data suggest that that the identity specification function of NGNs is more sensitive to context than is that of MASH1. In NCSCs, MASH1 is more sensitive to Notch-mediated inhibition of neurogenesis and cell cycle arrest, than are the NGNs. Thus, the two proneural genes differ in other functional properties besides the neuron subtype identities they can promote. These properties may explain cellular differences between MASH1- and NGN-dependent lineages in the timing of neuronal differentiation and cell cycle exit.

Genetic basis of the formation and identity of type I and type II neurons in Drosophila embryos

The embryonic peripheral nervous system of Drosophila contains two main types of sensory neurons: type I neurons, which innervate external sense organs and chordotonal organs, and type II multidendritic neurons. Here, we analyse the origin of the difference between type I and type II in the case of the neurons that depend on the proneural genes of the achaete-scute complex (ASC). We show that, in Notch- embryos, the type I neurons are missing while type II neurons are produced in excess, indicating that the type I/type II choice relies on Notch-mediated cell communication. In contrast, both type I and type II neurons are absent in numb- embryos and after ubiquitous expression of tramtrack, indicating that the activity of numb and the absence of tramtrack are required to produce both external sense organ and multidendritic neural fates. The analysis of string- embryos reveals that when the precursors are unable to divide they differentiate mostly into type II neurons, indicating that the type II is the default neuronal fate. We also report a new mutant phenotype where the ASC-dependent neurons are converted into type II neurons, providing evidence for the existence of one or more genes required for maintaining the alternative (type I) fate. Our results suggest that the same mechanism of type I/type II specification may operate at a late step of the ASC-dependent lineages, when multidendritic neurons arise as siblings of the external sense organ neurons and, at an early step, when other multidendritic neurons precursors arise as siblings of external sense organ precursors.