Tuesday, July 1, 2025 7/1/2025

Cell lineage and transcriptional analysis of the vertebrate neural plate border

Award Number: R01DE027538
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: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Cell lineage and transcriptional analysis of the vertebrate neural plate border - Both neural crest progenitors and ectodermal placode cells arise from the neural plate border (NPB). While the neural crest gives rise to the craniofacial skeleton, the placodes form the lens, ear and olfactory system; both contribute to cranial sensory ganglia. However, rather than being fixed to a neural crest or placodal fate, our results show that cells in the neural plate border appear to coexpress transcription factors characteristic of multiple lineages, ranging from neural crest to neural to placodal. Moreover, we find there is a stem cell niche within the dorsal neural tube that expresses pluripotency factors including Sall4, Nanog, Oct4, Klf4, and cMyc as confirmed in our single cell RNA-seq data. Thus, the question of what maintains stem cells with the potential to form neural crest, placode and neural tube derivatives at the neural plate border remains open. Our preliminary data suggest that Sall4 may form a feed-back loop with other multipotency genes, including Pou5f3/Oct4 and Sall1. Moreover, overexpression of Sall4 prevents neural crest specification and upregulates Oct4. To test the hypothesis that these pluripotency factors maintain multipotency of the neural plate border and that their downregulation is necessary for neural crest and/or placode specification, we will explore the effects of their gain and loss of function, identify enhancers that mediate their expression and examine dynamic changes in their gene expression during neural plate border maturation. To this end, the following aims will be performed. Aim 1: Effects of ectopic maintenance or loss of pluripotency factors on neural crest and placode development. We will test the role of pluripotency factors Sall4, Oct4, Nanog and Klf4 in vivo in neural plate border development using gain and loss of function approaches coupled with single cell RNA-seq. In particular, we will test the hypothesis that these pluripotency factors maintain the multipotency of the neural plate border and their downregulation is necessary for completion of neural crest specification. We will also examine other transcription factors to test their role in driving lineage specification at the neural plate border. Aim 2: Identification and cis-regulatory analysis of putative enhancers mediating expression of pluripotency factors and neural plate border transcriptional regulators. Detailed cis-regulatory analysis allows identification of active enhancers and their direct inputs, both positive and negative, thus informing upon gene regulatory network connections. We propose to use single cell ATAC-seq to identify putative regulatory elements active at the forming neural plate border, particularly those mediating expression of pluripotency factors and transcriptional regulators. Putative enhancers will be tested for inputs and their ability to drive expression. Aim 3: Dynamic analysis of enhancer-mediated expression during maturation of the neural plate border. By coupling live imaging with enhancer driven reporter expression, we propose to test dynamic changes in gene expression mediated by pluripotency genes and transcription factors. We will initially focus on enhancers that mediate expression of Pax7, Sox2 and Six1, characteristic of neural crest, neural and placodes, respectively.


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: 2025 ( Subtotal = $540,386 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	8	5/6/2025	NON-COMPETING CONTINUATION	$54,039
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	8	1/15/2025	NON-COMPETING CONTINUATION	$486,347
														Subtotal = $540,386

Issue Date FY: 2024 ( Subtotal = $529,579 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	7	1/2/2024	NON-COMPETING CONTINUATION	$486,347
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	7	5/17/2024	NON-COMPETING CONTINUATION	$43,232
2024	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	9/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $529,579

Issue Date FY: 2023 ( Subtotal = $540,386 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	6	12/22/2022	COMPETING CONTINUATION	$540,386
2023	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	12/7/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $540,386

Issue Date FY: 2022 ( Subtotal = $446,334 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	5	1/12/2022	SUPPLEMENT FOR EXPANSION	$47,252
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	5	5/4/2022	SUPPLEMENT FOR EXPANSION	$5,248
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	4/21/2022	NON-COMPETING CONTINUATION	$35,803
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	1/11/2022	NON-COMPETING CONTINUATION	$358,031
														Subtotal = $446,334

Issue Date FY: 2021 ( Subtotal = $523,810 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	4	2/25/2021	NON-COMPETING CONTINUATION	$52,382
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	1/19/2021	NON-COMPETING CONTINUATION	$471,428
														Subtotal = $523,810

Issue Date FY: 2020 ( Subtotal = $471,310 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	3	6/8/2020	SUPPLEMENT FOR EXPANSION	$73,497
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	1/15/2020	NON-COMPETING CONTINUATION	$358,031
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	2/18/2020	NON-COMPETING CONTINUATION	$39,782
														Subtotal = $471,310

Issue Date FY: 2019 ( Subtotal = $397,813 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	1/10/2019	NON-COMPETING CONTINUATION	$397,813
														Subtotal = $397,813

Issue Date FY: 2018 ( Subtotal = $397,813 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	1	4/10/2018	NEW	$5,938
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	2/20/2018	NEW	$391,875
														Subtotal = $397,813

Grand Total All Awards = $3,847,431

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Cell lineage and transcriptional analysis of the vertebrate neural plate border

Award Number: R01DE027538

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: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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