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Functions of Family with Sequence Similarity 20 - Member C (FAM20C) andMember A (FAM20A) in Amelogenesis and Dentinogenesis

Award Number: R01DE030081
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Phosphorylation is essential for the phosphorylated proteins to exert their functions in regulating the relevant biological processes. Recent studies have demonstrated that a protein kinase known as “FAM20C” (Family with sequence similarity 20 – member C), together with its paralog named “FAM20A”, plays key and non-redundant functions in phosphorylating serine residues within the Ser-x-Glu/pSer motifs of the secretory proteins, including enamel and dentin matrix proteins that are essential to amelogenesis and dentinogenesis. Although studies have confirmed that FAM20C resides in the Golgi apparatus, it is unclear as to how FAM20C, which does not possess a transmembrane domain, is retained in this organelle to exert its kinase function. While in vitro studies suggest that FAM20A may enhance the kinase activity of FAM20C, whether such functional interaction occurs in ameloblasts and odontoblasts in vivo remains to be determined; FAM20A mutations in humans or its inactivation in mice only affect enamel formation but have no pathological effect on dentin formation, whereas loss of FAM20C function leads to both enamel and dentin defects. The goals of this project are to determine 1) the molecular mechanisms that govern the Golgi-retention of FAM20C, and 2) how FAM20C interacts with FAM20A during amelogenesis and dentinogenesis. Preliminary studies have shown that 1) a FAM20C-related supramolecular complex was present in the cell extract but not in the culture medium when FAM20C was expressed in the transfected cells; 2) a similar large FAM20C-related protein band was also found in the total proteins extracted from the enamel organ (containing ameloblasts) and dental pulp (containing odontoblasts) of mouse teeth; 3) Fam20a-deficient mice developed enamel defects, but had no dentin abnormalities, whereas Fam20c-deficient mice had both enamel and dentin defects; 4) Fam20a-deficient mice had a dramatic reduction in the expression levels of genes encoding the enamel matrix proteins, but showed no expression changes in the genes encoding the major dentin matrix proteins; and 5) Fam20a deletion reduced the level of FAM20C protein in ameloblasts and odontoblasts. These findings lead to the hypothesis that FAM20C forms a supramolecular complex, through which this kinase is retained within the Golgi apparatus, and that FAM20A broadens the substrate spectrum of FAM20C and is required for the proper phosphorylation of the hydrophobic enamel matrix proteins. Two Aims are proposed to test this novel hypothesis: Aim 1 – to determine the mechanisms that govern the Golgi-retention of FAM20C in ameloblasts and odontoblasts. Aim 2 – to determine the functions of FAM20A and FAM20C in ameloblasts and odontoblasts. Successful completion of the proposed work will not only elucidate the molecular mechanisms by which FAM20C and FAM20A function in the phosphorylation of enamel and dentin matrix proteins, but may also provide clues for the development of therapeutic strategies for the clinical management of diseases caused by the FAM20C and FAM20A mutations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $382,383 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Oral Diseases and Disorders Research	000	4	8/16/2023	NON-COMPETING CONTINUATION	$382,383
														Subtotal = $382,383

Issue Date FY: 2022 ( Subtotal = $378,560 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	3	8/16/2022	NON-COMPETING CONTINUATION	$378,560
														Subtotal = $378,560

Issue Date FY: 2021 ( Subtotal = $411,427 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	2	8/10/2021	NON-COMPETING CONTINUATION	$411,427
														Subtotal = $411,427

Issue Date FY: 2020 ( Subtotal = $410,786 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	1	9/14/2020	NEW	$410,786
														Subtotal = $410,786

Grand Total All Awards = $1,583,156

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Functions of Family with Sequence Similarity 20 - Member C (FAM20C) andMember A (FAM20A) in Amelogenesis and Dentinogenesis

Award Number: R01DE030081

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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