Overexpression of guanylate cyclase activating protein 2 in rod photoreceptors in vivo leads to morphological changes at the synaptic ribbon

Guanylate cyclase activating proteins are EF-hand containing proteins that confer calcium sensitivity to retinal guanylate cyclase at the outer segment discs of photoreceptor cells. By making the rate of cGMP synthesis dependent on the free intracellular calcium levels set by illumination, GCAPs play a fundamental role in the recovery of the light response and light adaptation. The main isoforms GCAP1 and GCAP2 also localize to the synaptic terminal, where their function is not known. Based on the reported interaction of GCAP2 with Ribeye, the major component of synaptic ribbons, it was proposed that GCAP2 could mediate the synaptic ribbon dynamic changes that happen in response to light. We here present a thorough ultrastructural analysis of rod synaptic terminals in loss-of-function (GCAP1/GCAP2 double knockout) and gain-of-function (transgenic overexpression) mouse models of GCAP2. Rod synaptic ribbons in GCAPs−/− mice did not differ from wildtype ribbons when mice were raised in constant darkness, indicating that GCAPs are not required for ribbon early assembly or maturation. Transgenic overexpression of GCAP2 in rods led to a shortening of synaptic ribbons, and to a higher than normal percentage of club-shaped and spherical ribbon morphologies. Restoration of GCAP2 expression in the GCAPs−/− background (GCAP2 expression in the absence of endogenous GCAP1) had the striking result of shortening ribbon length to a much higher degree than overexpression of GCAP2 in the wildtype background, as well as reducing the thickness of the outer plexiform layer without affecting the number of rod photoreceptor cells. These results indicate that preservation of the GCAP1 to GCAP2 relative levels is relevant for maintaining the integrity of the synaptic terminal. Our demonstration of GCAP2 immunolocalization at synaptic ribbons at the ultrastructural level would support a role of GCAPs at mediating the effect of light on morphological remodeling changes of synaptic ribbons.

An Act of Assembly of Barbadoes to regulate sales at outcry and the proceedings of persons executing the office of Provost Marshall General ofthe said island and their under officers, 1763

An Act of Assembly of Barbadoes to regulate sales at outcry and the proceedings of persons executing the office of Provost Marshall General of the said island and their under officers (leaf 1) ; A state of some matters relative to the office of Provost Marshall, and to the passing of this bill (leaf 9) ; Observations drawn up by Jonathan Blenman Esq. his Majestys Atty. Gen. in Barbadoes ... on the Act as it had been first brought in 1761 (leaf 13) ; and two leaves laid in ; Power of attorney, granted to Christopher Scandrett, signed by Francis Reynolds and his son Thomas (25 April 1766) ; Petition of Francis Reynolds to the Lords Commissioners of Trade and Plantations (1766).

Sales at auction of property of the late Caleb Gannett Esq. of Cambridge, 1818

Eleven-page handwritten list of items sold from the estate of Caleb Gannett, dated May 29, 1818. Items are arranged by house location (such as "in the kitchen") and entries consist of the item name, the purchaser, and the price. The list includes a substantial section of "books in Office sold June 3, 1818." The verso of the last page includes the note: "Account of Sales at auction of the personal estate of C. Gannett- copied from auctioneer's book."

Account of articles included in auction sales--not inventoried, [1820 February]

One-page handwritten list of items sold at auction but not appraised.

Letter from Francis Sales to William Tudor,

One letter regarding the travel and activities of Peruvian politician Manuel Lorenzo de Vidaurre, including an including an excerpt of correspondence from Vidaurre in French.

Letter from Josiah Quincy to Francis Sales, 1835 October 12

Brief one-page handwritten letter to Francis Sales from Harvard President Josiah Quincy that accompanied the diploma for Sales's honorary master's degree.

Letter from Frances Sales to Josiah Quincy, 1835 October 22

One-page handwritten letter thanking President Quincy for his October 12, 1835 message and accompanying diploma. The document is pasted on the verso of a sheet also holding Sales's 1854 letter of resignation (HUG 1763 Box 1, Folder 3, Item 2).

Letter from Francis Sales, 1848 March 30

Handwritten copy of a brief letter in French presumably to Francois Arago congratulating him on his appointment in the French Provisional Government following the 1848 Revolution and the formation of the French Second Republic. Both Arago and Sales were from the Pyrénées-Orientales region of France.

Letter from Francis Sales to Dominique-Francois Arago, 1849 October 1

Three-and-a-half page handwritten copy of a letter in French from Francis Sales to Francois Arago on two folio-sized leaves. The letter begins with a short sketch of Sales's life and appears to be written to Arago in relation to his role as a political leader in the French Republic.

Letter from James Walker to Francis Sales, 1852 January 30

One-page handwritten letter from James Walker, in his capacity as a member of the Harvard Corporation, responding to Sales's letter of resignation due to health problems.

Autobiographical sketch of Francis Sales, 1853

Three-page handwritten draft of a biographical sketch of Francis Sales from his birth to immediately following his arrival in the United States. There is a penciled note on the last page: "Life of my father written by himself in 1853" presumably written by Mary Catherine Sales.

Copy of the Corporation vote regarding the death of Francis Sales, 1854 February 25

One-page handwritten copy of the Harvard Corporation vote of condolence following the death of Francis Sales.

Letter from Charles Sumner to Miss Sales, 1854 August 9

Handwritten letter of condolence from United States Senator Charles Sumner (Harvard AB 1830) to Francis Sales's daughter following her father's death. The mailing envelope accompanies the letter.