Due to the insistence of Frair Juan de Zumarraga and the viceroy Antonio de Mendoza, the first center of higher learning in America, was founded in Tlaltelolco and soon after there were humanist Indians. To Santa Cruz de Tlatelolco were sent the most advanced students from monastery schools.

The school was located inside the patio of the monastery of Santiago Tlatelolco, at first, it was a building of modest architecture constructed by the orders of Charles V, first owner of that house, later it was re-constructed and beautified by Friar Bernardino de Sahagun. This man spoke to the Indians in Nahuatl and wrote a dictionary Spanish-Nahuatl and Latin-Nahuatl in twelve volumes.

In 1551 the permit from the royal and pontific foundation of the University of Mexico was received, this university as well as all of the European institutions was considered canonical, which made the permit pass through the Pope , so the canonical foundation would be authorized. The university was opened on January 25, 1553; a solemn mass was sung in the church of San Pablo and from there a procession of schools took off.

The first president of the University was Don Juan Manuel de Negrete, and among, the first professors were: Friar Alonso from Veracruz, that imparted theology, Juan Garcia in arts, Francisco Cervantes de Salazar in subtleties and Blas de Bustamante in grammar. The lessons started to be given on June 5, 1553; there were about 100 founding students.

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