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Prdm16 and Mecom in mouse embryonic mandible and palate development.

Award Number: R15DE023982
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2018

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Prdm16 and Mecom in mouse embryonic mandible and palate development. - DESCRIPTION (provided by applicant): Orofacial clefting is one of the most common human birth defects (1-2 per 1000 live births). The social impact of these disorders is substantial with great financial and psychological costs to individuals. Approximately 70% of all clefting cases are isolated non-syndromic cases which exhibit complex, multifactorial inheritance with both multigenic and environmental contributions underlying its etiology. Pierre Robin Sequence (PRS)-type cleft palate (CP) is a common palate-extrinsic mechanism of clefting in which mandibular hypoplasia initiates a developmental sequence of events that culminates in failed palate shelf elevation and fusion and CP. Model organisms with gene mutations that result in craniofacial defects provide powerful in-roads into the cellular, molecular and developmental mechanisms at play during normal craniofacial development. We have shown that the Prdm16 transcription factor gene is required for normal palatogenesis in a novel recessive ENU- induced CP mutant, cleft secondary palate 1 (csp1). These mutants exhibit anterior-specific mandible hypoplasia and palate shelf elevation defects that model PRS-type CP. We have since generated and characterized a novel "conditional" gene trap null Prdm16 allele upon which this proposal is based. Previous studies and preliminary mandible-specific Prdm16 ablation studies support our hypothesis that palate- extrinsic Prdm16 function in the mandible is necessary and sufficient to allow normal regulation of downstream genes' expression required for formation of an intact secondary palate. Prdm16 has leukemogenic potential, a role in the maintenance of hematopoietic and neuronal stem cell progenitors and a well-established role in promoting brown adipose tissue identity versus skeletal muscle. Its paralog Mds1 and Evi1 complex locus (Mecom) is critical for mouse embryogenesis beyond embryonic day (E) 10.5 and hematopoietic stem cell function. A role for Mecom during mouse embryonic palate and mandible development has not been studied, although a loss-of-function Mecom allele results in widespread hypocellularity that, in part, affects neural crest-derived craniofacial prominences. In zebrafish prdm16 and prdm3 interact during development of the neurocranium and viscerocranium (jaw). Since Prdm16 and Mecom transcript isoforms are paralogous, and they are co-expressed in developing mandible and palate, we hypothesize that Prdm16 AND Mecom function together to regulate or "fine-tune" signaling pathways critical during mouse embryonic craniofacial development. To this end, we will assess the mechanism of clefting in Prdm16 null mutants (Aim 1). We also aim to identify tissue-specific Prdm16-dependent genes and direct transcriptional targets using comparative transcriptional profiling and targeted chromatin Immunoprecipitation-qPCR (ChIP- qPCR) studies in wild type versus null mutant embryonic mandible tissue (Aim 2). Finally, we will test our hypothesis that "Prdm16 and Mecom genetically interact" through double heterozygous intercross breeding of mice that carry Prdm16 and Mecom null alleles to generate embryos with varying gene dosage to be assessed for CP and abnormal craniofacial phenotypes (Aim 3).


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: 2019 ( Subtotal = $0 )
2019	2014	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Oral Diseases and Disorders Research	000	1	11/29/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $446,940 )
2014	2014	MIDWESTERN UNIVERSITY	555 31ST STREET	DOWNERS GROVE	IL	60515	DUPAGE	USA	Oral Diseases and Disorders Research	000	1	6/6/2014	NEW	$446,940
														Subtotal = $446,940

Grand Total All Awards = $446,940

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Prdm16 and Mecom in mouse embryonic mandible and palate development.

Award Number: R15DE023982

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2018

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