Mice with mutations in four nonreceptor tyrosine kinase genes, fyn, src, yes, and abl, were used to study the role of these kinases in long-term potentiation (LTP) and in the relation of LTP to spatial learning and memory. All four kinases were expressed in the hippocampus. Mutations in src, yes, and abl did not interfere with either the induction or the maintenance of LTP. However, in fyn mutants, LTP was blunted even though synaptic transmission and two short-term forms of synaptic plasticity, paired-pulse facilitation and post-tetanic potentiation, were normal. In parallel with the blunting of LTP, fyn mutants showed impaired spatial learning, consistent with a functional link between LTP and learning. Although fyn is expressed at mature synapses, its lack of expression during development resulted in an increased number of granule cells in the dentate gyrus and of pyramidal cells in the CA3 region. Thus, a common tyrosine kinase pathway may regulate the growth of neurons in the developing hippocampus and the strength of synaptic plasticity in the mature hippocampus.

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The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease. Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alphaGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alphaGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.