Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, longterm structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3ζ, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).The development of precise connections in the CNS is critically dependent on neural activity, which drives the elimination of inappropriate connections and the stabilization of appropriate ones. In the visual system of higher mammals, the refinement of initially imprecise axonal connections requires spontaneously generated activity early in development and visually driven activity later (1-4). Fine-tuning of neural connectivity is thought to result from changes in synaptic strength, driven by patterned impulse activity (1,2,5,6).To identify molecules critical for activity-dependent structural remodeling, we previously conducted an unbiased screen for mRNAs selectively regulated by blocking spontaneously generated activity in the developing cat visual system. This manipulation prevents the remodeling of retinal axons from each eye into layers within the lateral geniculate nucleus (LGN) (7-9). Although many known neural genes were not detectably regulated by activity blockade, this screen revealed to our surprise that members of the class I MHC protein family are expressed by neurons and are regulated by spontaneous and evoked neural activity (10). Neuronal class I MHC expression corresponds to well-characterized times and regions of activity-dependent development and plasticity of CNS connections, including retina, LGN, and hippocampus. Furthermore, the mRNA for CD3ζ [a class I MHC receptor subunit in the immune system (11)] is also expressed by neurons (10), consistent with its interaction with class I MHC during activity-dependent remodeling and plasticity. Although class I MHC is primarily known for its function in cell-mediated immune recognition, the above findings from our differential screen suggest that class I MHC molecules may play roles in structural and synaptic remodeling in the developing and mature CNS.

The mec-5 and mec-9 genes encode putative extracellular proteins that allow a set of six touch receptor neurons in C. elegans to respond to gentle touch. MEC-5 is a collagen made by the epidermal cells that surround the touch cells. Mutations causing touch insensitivity affect the Gly-X-Y repeats of this collagen. mec-9 produces two transcripts, the larger of which is expressed in the touch cells and two PVD neurons. This transcript encodes a protein with 5 Kunitz-type protease inhibitor domains, 6 EGF-like repeats (2 of the Ca(2+)-binding type), and a glutamic acid-rich region. Missense mutations causing touch insensitivity affect both the EGF-like and Kunitz domains. Since mec-9 loss of function mutations dominantly enhance the touch insensitive phenotype of several mec-5 mutations, MEC-5 and MEC-9 may interact. We propose that these proteins provide an extracellular attachment point for the mechanosensory channels of the touch cells.

Six touch receptor neurons with distinctive morphological features sense gentle touch in Caenorhabditis elegans. Previous studies have identified three genes (lin-32, unc-86 and mec-3) that regulate touch cell development. However, since other cell types also require these genes, we suspected that other genes help restrict the expression of touch cell characteristics to the six neurons seen in the wild type. To identify such genes, we have examined mutants defective in genes required for the development of other C. elegans cells for changes in the pattern of touch cell-specific features. Mutations in seven genes either reduce (lin-14) or increase (lin-4, egl-44, egl-46, sem-4, ced-3 and ced-4) the number of touch receptor-like cells. The combinatorial action of these genes, all of which are required for the production of many cell types, restrict the number of cells expressing touch receptor characteristics in wild-type animals by acting as positive and negative regulators and by removing cells by programmed cell death.

To identify genes regulating the development of the six touch receptor neurons, we screened the F2 progeny of mutated animals expressing an integrated mec-2::gfp transgene that is expressed mainly in these touch cells. From 2638 mutated haploid genomes, we obtained 11 mutations representing 11 genes that affected the production, migration, or outgrowth of the touch cells. Eight of these mutations were in known genes, and 2 defined new genes (mig-21 and vab-15). The mig-21 mutation is the first known to affect the asymmetry of the migrations of Q neuroblasts, the cells that give rise to two of the six touch cells. vab-15 is a msh-like homeobox gene that appears to be needed for the proper production of touch cell precursors, since vab-15 animals lacked the four more posterior touch cells. The remaining touch cells (the ALM cells) were present but mispositioned. A similar touch cell phenotype is produced by mutations in lin-32. A more severe phenotype; i.e., animals often lacked ALM cells, was seen in lin-32 vab-15 double mutants, suggesting that these genes acted redundantly in ALM differentiation. In addition to the touch cell abnormalities, vab-15 animals variably exhibit embryonic or larval lethality, cell degenerations, malformation of the posterior body, uncoordinated movement, and defective egg laying.