The identification and characterization of protein tyrosine phosphatases expressed in the developing rat brain

Mustafa Sahin, Yale University.

This is an Open Access Thesis


Previous studies of the developing nervous system have shown that cell-cell and cell-matrix interactions are involved in a variety of processes such as the proliferation, migration and differentiation of neurons. While many cell surface molecules have been identified, the signal transduction mechanisms through which they alter cellular responses are poorly understood. Recent studies have described a new and large family of enzymes, protein tyrosine phosphatases (PTPases), that may play a key role in transduction of cell surface events. Opposing the actions of protein tyrosine kinases (PTKs), PTPases may determine the state of tyrosine phosphorylation of a protein and regulate its function. Within the family of PTPases, two subgroups have been characterized: low molecular weight cytoplasmic (non-receptor) PTPases and high molecular weight transmembrane (receptor) PTPases. Receptor PTPases have fibronectin type III and/or immunoglobulin-like domains in their extracellular domains, suggesting that they may have dual functions: cell adhesion and signal transduction. Such molecules may play a role in cellular recognition events that mediate the accurate assembly of the nervous system.Using PCR with degenerate primers and a neonatal rat cortex cDNA library, we have identified seven PTPases expressed in the developing rat brain. Four of these are transmembrane PTPases: LAR, LRP, RPTP$\gamma$ and CPTP1. Three are non-receptor PTPases: PTP-1, P19-PTP and SHP. Within the embryonic and early postnatal brain, the seven PTPases have overlapping, yet unique distributions. The expression of each of these genes are regulated in a temporally and spatially restricted pattern. Two PTPase genes, CPTP1 and P19-PTP, are expressed in a developmentally-regulated pattern. These two PTPases are expressed at their highest levels during neurogenesis and neuronal differentiation and are markedly down-regulated during postnatal life. Both CPTP1 and P19-PTP are widely distributed in the developing brain. In contrast, a non-receptor protein tyrosine phosphatase, PTPH1, is found in a region-specific pattern. PTPH1 is expressed in all adult thalamic nuclei generated by the dorsal thalamus and is absent in the nuclei generated from the ventral thalamus.The abundance and differential regulation of PTPase genes expressed in the developing brain suggest that they play a role in cell-cell interactions mediating neural differentiation. The comparative analysis of the expression patterns presented in this dissertation can guide further biochemical and genetic experiments that would allow a better understanding of their precise cellular function.